Publications by authors named "Nils Kucher"

151 Publications

Fixed-Dose Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Pulmonary Embolism Associated with COVID-19.

Viruses 2022 Jul 22;14(8). Epub 2022 Jul 22.

Department of Angiology, University Hospital Zurich, 8091 Zurich, Switzerland.

Fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT) rapidly improves hemodynamic parameters and reverses right ventricular dysfunction caused by acute pulmonary embolism (PE). The effectiveness of USAT for acute PE associated with coronavirus disease 2019 (COVID-19) is unknown. The study population of this cohort study consisted of 36 patients with an intermediate-high- or high-risk acute PE treated with a fixed low-dose USAT protocol (r-tPA 10-20 mg/15 h). Of these, 9 patients tested positive for COVID-19 and were age-sex-matched to 27 patients without COVID-19. The USAT protocol included, beyond the infusion of recombinant tissue plasminogen activator, anti-Xa-activity-adjusted unfractionated heparin therapy (target 0.3-0.7 U/mL). The study outcomes were the invasively measured mean pulmonary arterial pressure (mPAP) before and at completion of USAT, and the National Early Warning Score (NEWS), according to which more points indicate more severe hemodynamic impairment. Twenty-four (66.7%) patients were men; the mean age was 67 ± 14 years. Mean  ±  standard deviation mPAP decreased from 32.3 ± 8.3 to 22.4 ± 7.0 mmHg among COVID-19 patients and from 35.4 ± 9.7 to 24.6 ± 7.0 mmHg among unexposed, with no difference in the relative improvement between groups ( = 0.84). Within 12 h of USAT start, the median NEWS decreased from six (Q1-Q3: 4-8) to three (Q1-Q3: 2-4) points among COVID-19 patients and from four (Q1-Q3: 2-6) to two (Q1-Q3: 2-3) points among unexposed ( = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Among patients with COVID-19-associated acute PE, mPAP rapidly decreased during USAT with a concomitant progressive improvement of the NEWS. The magnitude of mPAP reduction was similar in patients with and without COVID-19.
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http://dx.doi.org/10.3390/v14081606DOI Listing
July 2022

Acute on Chronic Thromboembolic Pulmonary Hypertension: Case Series and Review of Management.

J Clin Med 2022 Jul 21;11(14). Epub 2022 Jul 21.

Department of Pulmonology, University Hospital Zurich, 8091 Zurich, Switzerland.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of precapillary pulmonary hypertension classified as group 4 by the World Symposium on Pulmonary Hypertension (WSPH) and should be excluded during an episode of acute pulmonary embolism (PE). Patients presenting to emergency departments with sudden onset of signs and symptoms of acute PE may already have a pre-existing CTEPH condition decompensated by the new PE episode. Identifying an underlying and undiagnosed CTEPH during acute PE, while challenging, is an important consideration as it will alter the patients' acute and long-term management. Differential diagnosis and evaluation require an interdisciplinary expert team. Analysis of the clinical condition, the CT angiogram, and the hemodynamic situation are important considerations; patients with CTEPH usually have significantly higher sPAP at the time of index PE, which is unusual and unattainable in the context of acute PE and a naïve right ventricle. The imaging may reveal signs of chronic disease such as right ventricle hypertrophy bronchial collaterals and atypical morphology of the thrombus. There is no standard for the management of acute on chronic CTEPH. Herein, we provide a diagnostic and management algorithm informed by several case descriptions and a review of the literature.
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http://dx.doi.org/10.3390/jcm11144224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317831PMC
July 2022

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

Lancet Haematol 2022 Aug 30;9(8):e585-e593. Epub 2022 Jun 30.

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

Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.

Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.

Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.

Funding: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.
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http://dx.doi.org/10.1016/S2352-3026(22)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243568PMC
August 2022

Impact of concomitant popliteal vein thrombosis in patients with acute iliofemoral deep vein thrombosis treated with endovascular early thrombus removal.

Vasa 2022 Jul 1. Epub 2022 Jul 1.

Department of Internal Medicine, HFR Fribourg - Cantonal Hospital, Fribourg, Switzerland.

Catheter-based thrombus removal (CBTR) reduces the risk of moderate to severe post-thrombotic syndrome (PTS) in patients with acute iliofemoral deep vein thrombosis (IF-DVT). However, the impact of concomitant popliteal DVT on clinical and duplex sonographic outcomes is unknown. In this post-hoc analysis including the entire cohort of the randomized controlled BERNUTIFUL trial (48 patients), we compared clinical (incidence/severity of PTS assessed by Villalta score and revised venous clinical severity scores, rVCSS), disease-specific quality-of-life (QOL, CIVIQ-20 survey) and duplex sonographic outcomes (patency, reflux, post-thrombotic lesions) at 12 months follow-up between patients with IF-DVT and concomitant popliteal DVT treated by CBTR. Overall, 48 IF-DVT patients were included (48% men, median age of 50 years), of whom 17 (35%) presented popliteal DVT. At baseline, patients popliteal DVT were older, had a higher body mass index and more important leg swelling. At 12 months, freedom from PTS (93% vs 87%, P=0.17), median total Villalta score (1 vs 1.5; P=0.46), rVCSS (2 vs 1.5, P=0.5) and disease-specific QOL (24 points vs 24 points, P=0.72) were similar between patient and popliteal DVT, respectively. Duplex sonographic outcomes were similar, except for more frequent popliteal post-thrombotic lesions and reflux (P=0.02) in patients popliteal DVT. Relevant clinical outcomes 1 year after successful CBTR were favorable, regardless of the presence or absence of concomitant popliteal DVT. However, post-thrombotic popliteal vein lesions and reflux are more frequent in IF-DVT patients with popliteal involvement. Their impact on long-term outcomes remains to be investigated.
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http://dx.doi.org/10.1024/0301-1526/a001017DOI Listing
July 2022

Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study.

Am Heart J 2022 Sep 16;251:43-53. Epub 2022 May 16.

Center for Thrombosis and Heamostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece. Electronic address:

Background: Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE).

Methods And Results: The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium.

Conclusions: Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future.
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http://dx.doi.org/10.1016/j.ahj.2022.05.011DOI Listing
September 2022

Major adverse limb events in patients with femoro-popliteal and below-the-knee peripheral arterial disease treated with either sirolimus-coated balloon or standard uncoated balloon angioplasty: a structured protocol summary of the "SirPAD" randomized controlled trial.

Trials 2022 Apr 21;23(1):334. Epub 2022 Apr 21.

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

Background: Peripheral arterial disease is a progressive atherosclerotic disease with symptoms ranging from an intermittent claudication to acute critical limb ischemia and amputations. Drug-coated balloons and stents were developed to prevent neo-intimal proliferation and restenosis after percutaneous transluminal angioplasty. Randomized controlled trials showed that drug-coated, notably paclitaxel-coated, devices reduce restenosis, late lumen loss, and the need for target lesion re-vascularization compared with uncoated ones. However, the size of these trials was too small to prove superiority for "hard" clinical outcomes. Moreover, available studies were characterized by too restrictive eligibility criteria. Finally, it remains unclear whether paclitaxel-coated balloons may impair long-term survival. Alternative drug-coated balloons, the so-called limus-based analogs, have been approved for clinical use in patients with peripheral arterial disease. By encapsulating sirolimus in phospholipid drug nanocarriers, they optimize adhesion properties of sirolimus and provide better bioavailability.

Methods: In this investigator-initiated all-comer open-label phase III randomized controlled trial, we will evaluate whether sirolimus-coated balloon angioplasty is non-inferior and eventually superior, according to a predefined hierarchical analysis, to uncoated balloon angioplasty in adults with infra-inguinal peripheral arterial disease requiring endovascular angioplasty. Key exclusion criteria are pregnancy or breastfeeding, known intolerance or allergy to sirolimus, and participation in a clinical trial during the previous 3 months. The primary efficacy outcome is the composite of two clinically relevant non-subjective "hard" outcomes: unplanned major amputation of the target limb and endovascular or surgical target lesion re-vascularization for critical limb ischemia occurring within 1 year of randomization. The primary safety outcome includes death from all causes.

Discussion: By focusing on clinically relevant outcomes, this study will provide useful information on the efficacy and safety of sirolimus-coated balloon catheters for infra-inguinal peripheral arterial disease in a representative ("all-comer") population of unselected patients. As regulatory agencies had raised safety concerns in patients exposed to paclitaxel-coated devices (versus uncoated ones), collect mortality data up to 5 years after randomization will be collected.

Trial Registration: ClinicalTrials.gov NCT04238546.
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http://dx.doi.org/10.1186/s13063-022-06242-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9027348PMC
April 2022

A novel management strategy for treatment of pelvic venous disorders utilizing a clinical screening score and non-invasive imaging.

Vasa 2022 May 13;51(3):182-189. Epub 2022 Apr 13.

Department of Angiology, University Hospital Zurich, Switzerland.

Treatment of pelvic venous disorders (PVD) including pelvic congestion syndrome (PCS) are often delayed due to its varying clinical manifestations. Patient referral was based on a literature- and personal experience-derived clinical "PCS screening score" (higher score points indicate greater likelihood with a maximum score of 10 points). We studied consecutive women who were (i) referred for vascular assessment and treatment to the University Hospital Zurich (2017-2021), (ii) had a PCS score ≥3 points, (iii) had evidence of obstructive or non-obstructive PVD by duplex sonography or cross-sectional imaging, and (iv) underwent endovascular therapy. The primary outcome was change in symptom severity after endovascular therapy: (i) freedom from symptoms, (ii) improvement with residual symptoms, (iii) no improvement. We included 43 women (mean age 36 years): 81% had previous pregnancy, 19% endometriosis. The median PCS score was 7 (IQR 5-9) points. Chronic lower-abdominal pain was the leading symptom in 86% patients, followed by recurrent leg (9%) and vulvar (5%) varicosities. The main PVD pathologies were ovarian vein insufficiency (61%), internal iliac vein insufficiency (9%), or a combination of both (30%), whereas 42% had a deep venous obstruction of the inferior vena cava, common iliac or left renal veins. Endovascular therapy included ovarian vein embolization (86%), internal iliac vein embolization (9%), and venous stent placement (35%). After a median of 4 (IQR 1-8) months from endovascular treatment, 40 (93%) patients reported improvement of the leading symptom, and 14 (33%) were symptom-free. Complications included re-intervention for stent stenosis (13%, all post-thrombotic), coil-migration into the left renal vein (7%, all retrieved), and transient pelvic sclerotherapy-induced thrombophlebitis (2%). Endovascular therapy following a diagnostic approach, which included a PCS screening tool and non-invasive imaging, appeared to be highly effective and was associated with a low rate of complications.
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http://dx.doi.org/10.1024/0301-1526/a001001DOI Listing
May 2022

Cardiac and Cerebral Arterial Complications of Lemierre Syndrome: Results from a Systematic Review and Individual Patient Data Meta-analysis.

Hamostaseologie 2022 Mar 7. Epub 2022 Mar 7.

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

Background:  Lemierre syndrome is a potentially life-threatening disease, which affects otherwise healthy young adults and adolescents. It is characterized by acute neck vein thrombosis and septic embolism, usually complicating a bacterial infection. Data on the syndrome are sparse, particularly concerning arterial complications.

Methods:  We evaluated the frequency and patterns of cerebral arterial and cardiac involvement ("arterial complications") in an individual patient level cohort of 712 patients, representing all cases described over the past 20 years in the medical literature who fulfilled the criteria: (1) bacterial infection in the neck/head site and (2) objectively confirmed thrombotic complication or septic embolism. The study outcomes were defined as all-cause in-hospital deaths and the occurrence of clinical sequelae at discharge or in the postdischarge period.

Results:  A total of 55 (7.7%) patients had an arterial complication. The most frequent arterial complications were carotid involvement (52.7%), stroke (38.2%), and pericardial complications (20%). Patients with an arterial involvement were more likely to be treated with a greater number of antibiotics (23 vs. 10%) and to receive anticoagulation. In addition, patients with arterial complications had a greater risk of all-cause death ( = 20/600, 3.3% vs.  = 6/52, 12%; odds ratio [OR]: 3.8; 95% confidence interval [CI]: 1.5-9.9) and late clinical sequelae ( = 49/580, 9.0% vs.  = 15/46, 35%; OR: 5.2; 95% CI: 2.65-10.37).

Conclusions:  While Lemierre syndrome is known to be primarily characterized by venous thromboembolic events, our results suggest that local or distant arterial complications may occur in approximately one-tenth of patients and may be associated with a greater risk of long-term sequelae and death.
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http://dx.doi.org/10.1055/a-1694-8723DOI Listing
March 2022

Deaths related to pulmonary embolism and cardiovascular events before and during the 2020 COVID-19 pandemic: An epidemiological analysis of data from an Italian high-risk area.

Thromb Res 2022 04 20;212:44-50. Epub 2022 Feb 20.

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

Background: Pulmonary embolism is a known complication of coronavirus disease 2019 (COVID-19). Epidemiological population data focusing on pulmonary embolism-related mortality is limited.

Methods: Veneto is a region in Northern Italy counting 4,879,133 inhabitants in 2020. All ICD-10 codes from death certificates (1st January 2018 to 31st December 2020) were examined. Comparisons were made between 2020 (COVID-19 outbreak) and the average of the two-year period 2018-2019. All-cause, COVID-19-related and the following cardiovascular deaths have been studied: pulmonary embolism, hypertensive disease, ischemic heart disease, atrial fibrillation/flutter, and cerebrovascular diseases.

Results: In 2020, a total of 56,412 deaths were recorded, corresponding to a 16% (n = 7806) increase compared to the period 2018-2019. The relative percentage increase during the so-called first and second waves was 19% and 44%, respectively. Of 7806 excess deaths, COVID-19 codes were reported in 90% of death certificates. The percentage increase in pulmonary embolism-related deaths was 27% (95%CI 19-35%), 1018 deaths during the year 2020, compared to 804 mean annual deaths in the period 2018-2019. This was more evident among men, who experience an absolute increase of 147 deaths (+45%), than in women (+67 deaths; +14%). The increase was primarily driven by deaths recorded during the second wave (+91% in October-December). An excess of deaths, particularly among men and during the second wave, was also observed for other cardiovascular diseases, notably hypertensive disease, atrial fibrillation, cerebrovascular disease, and ischemic heart disease.

Conclusions: We observed a considerable increase of all-cause mortality during the year 2020. This was mainly driven by COVID-19 and its complications. The relative increase in the number of pulmonary embolism-related deaths was more prominent during the second wave, suggesting a possible underdiagnosis during the first wave.
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http://dx.doi.org/10.1016/j.thromres.2022.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8858636PMC
April 2022

Transient perivascular inflammation of the carotid artery (TIPIC) syndrome.

Vasa 2022 Mar 8;51(2):71-77. Epub 2022 Feb 8.

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

: The Transient Perivascular Inflammation of the Carotid artery (TIPIC) syndrome is presumably a very rare disease characterized by a local transient inflammation of the tissue around the carotid artery. Its pathophysiology remains unknown. We performed an updated study of TIPIC syndrome cases in the setting of a multinational collaborative study. : This study was conducted as an observational multinational retrospective individual patient level cohort study. Information from all known cases diagnosed with TIPIC syndrome in the literature (2005-2020) was collected after a semi-structured literature search of PubMed and Web of Science. We also collected unpublished information of patients from French, Swiss, and Italian vascular medicine or radiology departments. : A total of 72 patients were included and served for data analysis: 42 (58.3%) were women; the mean age was 47.9 (SD=11.4) years. Symptoms were unilateral in 92% of patients and 81.4% required pain killers. At baseline, irrespective of the imaging method used, the median thickness of the carotid lesions was 5 (Q1-Q3: 4-7; range: 2-11) mm and the median length of the lesion was 20 (Q1-Q3: 10-30; range: 3-50) mm. We found a positive linear correlation between thickness and length. At follow-up, the thickness of the carotid lesions decreased to a median of 2 (Q1-Q3: 1-3; range: 0-6) mm; the length decreased to a median 10 (Q1-Q3: 5-15; range: 0-41) mm. A linear correlation between baseline and follow-up values was observed for both thickness and length measurements. Symptoms disappeared after a median of 14 (Q1-Q3: 10-15) days. Thirteen patients experienced a recurrence after a median follow-up of 6 (Q1-Q3: 2-12) months. : The present analysis elucidates clinical and sonographic characteristics of TIPIC syndrome, indicating the benign nature of this condition. A future international registry will study the long-term course of the disease.
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http://dx.doi.org/10.1024/0301-1526/a000989DOI Listing
March 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

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 2022 02 13;20(2):409-421. Epub 2021 Dec 13.

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 Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) multinational cross-sectional study reported that only approximately 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 thromboprophylaxis globally. We focused on: (a) the frequency of patients with an indication to thromboprophylaxis according with individual models; (b) the use of adequate thromboprophylaxis; and (c) reported contraindications to thromboprophylaxis. Observational nonrandomized 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% confidence interval [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: 50.7-81.1, I 98%), 44.9% in Africa (95% CI: 31.8-58.4, 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299991PMC
February 2022

Role of age, sex, and specific provoking factors on the distal versus proximal presentation of first symptomatic deep vein thrombosis: analysis of the SWIss Venous ThromboEmbolism Registry (SWIVTER).

Intern Emerg Med 2022 04 3;17(3):799-803. Epub 2021 Nov 3.

Department of Angiology, University Hospital Zurich, Raemistrasse 100, RAE C 13, 8091, Zurich, Switzerland.

We aimed to evaluate the impact of age, sex, and their interactions with provoking risk factors for deep vein thrombosis (DVT). In addition, we intended to provide additional insights on risk factors associated with the isolated distal versus proximal presentation of first symptomatic acute DVT, both being characterized by different prognosis. In the present analysis from the SWIss Venous ThromboEmbolism Registry (SWIVTER), we compared demographic and baseline characteristics in patients with isolated distal (n = 184; 35%) versus proximal (n = 346) DVT of the lower limbs without symptomatic pulmonary embolism, and identified factors related with the presenting thrombosis location. In the overall population, mean age was 59 ± 19 years, 266 (50%) were women, 106 (20%) patients had cancer, 86 (16%) recent surgery, and 52 (10%) acute infection/sepsis. In a multivariable analysis, recent surgery [odds ratio (OR) 2.92, 95% confidence interval (CI) 1.80-4.73] was independently associated with a diagnosis of isolated distal DVT, whereas cancer (OR 2.01, 95% CI 1.20-3.35), male sex aged 41 to 75 years (OR 2.21, 95% CI 1.33-3.67), and acute infection/sepsis (OR 2.71, 95% CI 1.29-5.66) with a diagnosis of proximal DVT. In SWIVTER, age, sex, and several provoking risk factors for VTE appeared to be related with the presenting location of first symptomatic DVT. Cancer, male sex, and acute infection/sepsis were associated with a proximal location of DVT, whereas recent surgery was associated with a distal presentation, likely acting as confounders for the association between thrombosis location and prognosis.
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http://dx.doi.org/10.1007/s11739-021-02878-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9018645PMC
April 2022

Association of Intrarenal Resistance Index and Systemic Atherosclerosis After Kidney Transplantation.

In Vivo 2021 Nov-Dec;35(6):3369-3375

Vascular Center, Cantonal Hospital Baden, Baden, Switzerland;

Background/aim: Patients after kidney transplants are at risk of cardiovascular morbidity. An elevated resistance index (RI) is associated with renal graft failure, while a decreased RI can be due to a renal artery stenosis. The RI can also be measured in the carotid artery. Whether a correlation between intrarenal RI after kidney transplant in adult patients and the RI of the internal carotid artery exists is still unclear.

Patients And Methods: In this prospective cross-sectional study, RI of kidney transplants and of the internal carotid artery were measured with duplex sonography. Carotid intima-media thickness as well as the Framingham risk score and the Augmentation index, all known markers of atherosclerosis, were assessed. Correlations between the RI in Carotid artery and the RI of the kidney transplant were based on Spearmen test with the level of significance set at p<0.05.

Results: Ninety-eight consecutive patients [60% male, mean age of 48.7 (±15.6)] were included. The mean interval after transplantation was 27.5 (±8.5) months and mean serum creatinine was 308 (±220.3) mmol/ml The RI of the internal carotid artery and the renal transplant were significantly correlated (p<0.05). A correlation between the RIs and the Augmentation Index was found.

Conclusion: The RI of the kidney transplant is correlated with the RI of the carotid artery and to markers of general atherosclerosis. This observation may be helpful to identify patients after kidney transplant with higher risk for cardiovascular events and gain indirect information on transplant renal artery stenosis.
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http://dx.doi.org/10.21873/invivo.12635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8627733PMC
October 2021

Pulmonary embolism and deep vein thrombosis: Similar but different.

Thromb Res 2021 Oct 19;206:88-98. Epub 2021 Aug 19.

Institute of Pharmacology, University of Bern, Switzerland. Electronic address:

Introduction: Pulmonary embolism (PE) and deep vein thrombosis (DVT), the two clinical manifestations of venous thromboembolism (VTE), constitute a major global burden of cardiovascular disease. They are often referred to as one disease but several patient characteristics, risk factors, real-world treatment, and clinical outcomes may differ substantially between PE and DVT alone.

Materials And Methods: We conducted a narrative review of the state-of-the-art literature on the topic of PE and DVT alone using PubMed, Google scholar, and MEDLINE databases and the most established international consensus statement guidelines for the management of VTE, focusing on the recommendations for diagnosis and treatment but also including epidemiological and clinical characteristics of VTE, highlighting similarities and differences between PE and DVT alone.

Results: Several patient characteristics, risk factors, clinical manifestations, and outcomes differ substantially between PE versus DVT alone. Nevertheless, recommendations for both diagnosis and treatment are strikingly similar in the current guidelines for the management of DVT and PE, except for the indication for advanced reperfusion therapies.

Conclusions: The differences in risk factors, clinical manifestations, and clinical outcomes between patients with PE versus DVT alone are only marginally addressed in the current consensus guidelines. More data is needed allowing proposal of evidence-based adjustments in the diagnostic and therapeutic strategies for these two manifestations of VTE. Tailored risk stratification and individualized management strategies for patients with PE and DVT alone may lead to a better prognosis, less recurrence and complications, and possibly to a gain of quality-adjusted life years in patients with VTE.
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http://dx.doi.org/10.1016/j.thromres.2021.08.015DOI Listing
October 2021

[Trends in mortality related to pulmonary embolism in the DACH countries].

Med Klin Intensivmed Notfmed 2021 Aug 24. Epub 2021 Aug 24.

Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, Langenbeckstraße 1, 55131, Mainz, Deutschland.

Background: Pulmonary embolism (PE)-related mortality is decreasing worldwide.

Aim: Little is known about the burden imposed by pulmonary embolism for Germany, Austria and Switzerland (DACH countries).

Materials And Methods: We aimed to assess pulmonary embolism-related mortality and time trends for the DACH countries based on data from the WHO Mortality Database. Deaths were considered pulmonary embolism-related if the International Classification of Disease-10 code for acute pulmonary embolism or any code for deep or superficial vein thrombosis was listed as the primary cause of death.

Results: Between 2000 and 2015, age-standardized annual pulmonary embolism-related mortality rates decreased linearly from 15.6 to 7.8 deaths per 1000 population. In the 5‑year period between 2012 and 2016, an average of 9127 pulmonary embolism-related deaths occurred annually in the DACH countries with a population of 98,273,329. Interestingly, pulmonary embolism-related mortality rates were considerably higher among women aged 15-55 years compared to age-matched men.

Conclusion: The observed decreasing trends in pulmonary embolism-related mortality might reflect improved management of the disease including new treatment options as well as advances in imaging technologies. However, pulmonary embolism remains a substantial contributor to total mortality, especially among women aged 15-55 years. For this reason, campaigns to increase physician and public awareness are urgently required to further improve the management and treatment of this preventable thrombotic disorder, which still remains the leading preventable cause of death.
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http://dx.doi.org/10.1007/s00063-021-00854-9DOI Listing
August 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

Thrombosis and Dissection of the Abdominal Arteries Associated with Infarcts of Solid Organs in a Patient with COVID-19: A Novel Clinical Entity.

Hamostaseologie 2022 Jun 22;42(3):195-197. Epub 2021 Jun 22.

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

The clinical spectrum of patients with coronavirus disease 2019 (COVID-19) ranges from asymptomatic cases to severe pneumonia with acute respiratory distress syndrome. COVID-19 is associated with an increased risk of thromboembolic complications, notably pulmonary embolism and deep vein thrombosis. Arterial cardiovascular complications and myocarditis have also been described in association with COVID-19, but appear to be less prevalent. In this report of a 57-year-old man with multiple splanchnic infarctions, arterial dissections and COVID-19 as the sole potential trigger, we describe a novel type of complications and put it in the context of a growing literature on this topic.
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http://dx.doi.org/10.1055/a-1476-7907DOI Listing
June 2022

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

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

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

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

Reversal of cardiopulmonary exercise intolerance in patients with post-thrombotic obstruction of the inferior vena cava.

Thromb Res 2021 Dec 9;208:219-225. Epub 2021 Apr 9.

Clinic for Angiology, University Hospital Zurich, Switzerland. Electronic address:

Background: It is unclear whether cardiopulmonary exercise intolerance in patients with chronic obstruction of the inferior vena cava (IVC) is reversible following endovascular IVC reconstruction.

Methods: In 17 patients (mean age 45 ± 15 years, 71% men) with post-thrombotic syndrome due to IVC obstruction and preserved left ventricular ejection fraction (mean 58 ± 3%), we performed cardiopulmonary exercise testing before and 3 months after IVC reconstruction (mean 4.1 ± 1.5 implanted stents). The median time from latest episode of deep vein thrombosis to intervention was 150 (interquartile range 102-820) days.

Results: At baseline, 12 (71%) patients reported New York Heart Association (NYHA) class II or III symptoms, 76% did not achieve >85% of predicted oxygen uptake at peak exercise (mean 61.8 ± 13.7%). After IVC reconstruction, the following changes were observed at anaerobic threshold: work rate increased by 14.6 W, 95%CI (-0.7; 30.0), oxygen uptake increased by 1.8 ml/kg, 95%CI (0.3; 3.3). Oxygen pulse increased by 1.95 ml per beat, 95%CI (1.12; 2.78), corresponding to a mean relative increase of 22.5%, 95%CI (12.4; 32.7) (p < 0.001). The following changes were observed at peak exercise: work rate increased by 48.1 W, 95%CI (27.8; 68.4), oxygen uptake increased by 6.4 ml/kg, 95%CI (3.8; 9.1). Oxygen pulse increased by 2.68 ml per beat, 95%CI (1.60; 3.76), corresponding to a mean relative increase of 29.4%, 95%CI (17.7; 41.2) (p < 0.001). At follow-up, 5 (29%) patients remained in NYHA class II.

Conclusions: In patients with chronic IVC obstruction, cardiopulmonary exercise intolerance as a result of impaired cardiac filling is at least partially reversible following endovascular IVC reconstruction.

Study Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02433054.
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http://dx.doi.org/10.1016/j.thromres.2021.03.025DOI Listing
December 2021

Clinical presentation and long-term follow-up of 45 patients with Mondor disease: A single-center longitudinal study.

Vasc Med 2021 08 8;26(4):409-414. Epub 2021 Apr 8.

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

Mondor disease is characterized by an acute painful thrombophlebitis occurring at specific anatomical sites. Data on its incidence, characteristics of clinical presentation, and course are unavailable to date. We studied the course of Mondor disease in patients diagnosed and followed at the University Hospital Zurich (Switzerland) between 2004 and 2020. The primary study outcomes were a diagnosis of active cancer either at the time of clinical diagnosis of Mondor disease or within 1 year, as well as 1-year all-cause death and recurrent Mondor disease. We included 45 patients and classified them into one of the three Mondor disease subgroups: thoracic ( = 26), penile ( = 12), or axillary ( = 7). The median age was 39 (Q1-Q3: 30-45) years and 44% of patients were men. Surgery was the likely cause of Mondor disease in 53.8% of patients with a thoracic form, 41.7% of those with a penile location, and all of those with an axillary location. Known active cancer was present in nine (20%) of 45 patients at baseline. One-year follow-up was available for 43 patients (median 94 months), whereas 6-month data were available for the remaining two patients. During the available follow-up, no patient had a new diagnosis of cancer. In conclusion, one in five patients with Mondor disease had known cancer at the time of diagnosis. During follow-up, the rate of new cancer diagnosis and death was negligible, providing reassurance about the good prognosis of this condition. Based on these preliminary data, extended cancer screening besides what is recommended by current guidelines for the general population might not be necessary in patients with Mondor disease.
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http://dx.doi.org/10.1177/1358863X211000420DOI Listing
August 2021

Sex differences in Lemierre syndrome: Individual patient-level analysis.

Thromb Res 2021 06 6;202:36-39. Epub 2021 Mar 6.

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

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http://dx.doi.org/10.1016/j.thromres.2021.03.002DOI Listing
June 2021

Self-Expandable Nitinol Stents for the Treatment of Nonmalignant Deep Venous Obstruction.

Circ Cardiovasc Interv 2020 12 4;13(12):e009673. Epub 2020 Dec 4.

Clinic for Angiology, University Hospital Zurich, Switzerland (T.S., S.G., L.M., R.K., S.B., N.K.).

Background: Angioplasty with stent placement is a therapeutic option for patients with acute thrombotic, postthrombotic, and nonthrombotic obstruction of the iliofemoral veins or inferior vena cava. Previous studies of steel-alloy stents described variable patency rate across indications.

Methods: The prospective Swiss Venous Stent Registry includes patients treated with self-expandable nitinol stents for deep venous obstruction. Routine follow-up visits include serial duplex ultrasound for stent patency assessment. The primary outcome was primary stent patency. The secondary outcome was venous thromboembolisms. We studied the rate of stent occlusion and potentially contributing factors.

Results: We included 379 patients: 160 with acute thrombotic, 193 with postthrombotic, and 26 with nonthrombotic deep vein obstruction. The mean age was 46±18 years; 55% were women. The cumulative 3-year primary patency rate was 80.5% (95% CI, 73.0%-88.0%) for acute thrombotic, 59.2% (95% CI, 50.4%-68.0%) for postthrombotic, and 100% for nonthrombotic obstruction (log-rank, <0.0001). Annualized rates of stent occlusion or venous thromboembolism were 7.8 (acute thrombotic), 15.0 (postthrombotic), and 0 (nonthrombotic) events/100 patient-years. In a multivariable Cox regression model, postthrombotic femoral veins at baseline (hazard ratio, 2.64 [95% CI, 1.53-4.56]) and the number of stents (hazard ratio, 1.22 [95% CI, 1.06-1.40]) were associated with stent occlusion after conditioning for age, sex, and clinically relevant factors.

Conclusions: The rate of stent occlusion (patency loss) and venous thromboembolism varies substantially across indications, also with dedicated venous nitinol stents. Patients with postthrombotic femoral veins and those who received multiple stents were characterized by the highest risk. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02433054.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009673DOI Listing
December 2020

Fever management in COVID-19 patients.

Minerva Anestesiol 2021 01 24;87(1):1-3. Epub 2020 Nov 24.

Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Brussels, Belgium.

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http://dx.doi.org/10.23736/S0375-9393.20.15195-2DOI Listing
January 2021

Clinical Outcomes of Incidental Venous Thromboembolism in Cancer and Noncancer Patients: The SWIss Venous ThromboEmbolism Registry (SWIVTER).

Thromb Haemost 2021 May 17;121(5):641-649. Epub 2020 Nov 17.

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

Objective:  In patients with cancer-associated venous thromboembolism (VTE), the risk of recurrence is similar after incidental and symptomatic events. It is unknown whether the same applies to incidental VTE not associated with cancer.

Methods And Results:  We compared baseline characteristics, anticoagulation therapy, all-cause mortality, and VTE recurrence rates at 90 days between patients with incidental ( = 131; 52% without cancer) and symptomatic ( = 1,931) VTE included in the SWIss Venous ThromboEmbolism Registry (SWIVTER). After incidental VTE, 114 (87%) patients received anticoagulation therapy for at least 3 months. The mortality rate was 9.2% after incidental and 8.4% after symptomatic VTE for hazard ratio (HR) 1.10 (95% confidence interval [CI] 0.49-2.50). After adjustment for competing risk of death, recurrence rate was 3.1 versus 2.8%, respectively, for sub-HR 1.07 (95% CI 0.39-2.93). These results were consistent among cancer (mortality: 15.9% vs. 12.6%; HR 1.32, 95% CI 0.67-2.59; recurrence: 4.8% vs. 4.7%; HR 1.02, 95% CI 0.30-3.42) and noncancer patients (mortality: 2.9% vs. 2.1%; HR 1.37, 95% CI 0.33-5.73; recurrence: 1.5% vs. 2.3%; HR 0.63, 95% CI 0.09-4.58). Patients with incidental VTE who received anticoagulation therapy for at least 3 months had lower mortality (4% vs. 41%) and recurrence rate (1% vs. 18%) compared with those who did not.

Conclusion:  In SWIVTER, more than half of incidental VTE events occurred in noncancer patients who often received anticoagulation therapy. Among noncancer patients, early mortality and recurrence rates were similar after incidental versus symptomatic VTE. Our findings suggest that anticoagulation therapy for incidental VTE may be beneficial regardless of the presence of cancer.
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http://dx.doi.org/10.1055/s-0040-1720977DOI Listing
May 2021

Age-sex specific pulmonary embolism-related mortality in the USA and Canada, 2000-18: an analysis of the WHO Mortality Database and of the CDC Multiple Cause of Death database.

Lancet Respir Med 2021 01 12;9(1):33-42. Epub 2020 Oct 12.

Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.

Background: Pulmonary embolism (PE)-related mortality is decreasing in Europe. However, time trends in the USA and Canada remain uncertain because the most recent analyses of PE-related mortality were published in the early 2000s.

Methods: For this retrospective epidemiological study, we accessed medically certified vital registration data from the WHO Mortality Database (USA and Canada, 2000-17) and the Multiple Cause of Death database produced by the Division of Vital Statistics of the US Centers for Disease Control and Prevention (CDC; US, 2000-18). We investigated contemporary time trends in PE-related mortality in the USA and Canada and the prevalence of conditions contributing to PE-related mortality reported on the death certificates. We also estimated PE-related mortality by age group and sex. A subgroup analysis by race was performed for the USA.

Findings: In the USA, the age-standardised annual mortality rate (PE as the underlying cause) decreased from 6·0 deaths per 100 000 population (95% CI 5·9-6·1) in 2000 to 4·4 deaths per 100 000 population (4·3-4·5) in 2006. Thereafter, it continued to decrease to 4·1 deaths per 100 000 population (4·0-4·2) in women in 2017 and plateaued at 4·5 deaths per 100 000 population (4·4-4·7) in men in 2017. Among adults aged 25-64 years, it increased after 2006. The median age at death from PE decreased from 73 years to 68 years (2000-18). The prevalence of cancer, respiratory diseases, and infections as a contributing cause of PE-related death increased in all age categories from 2000 to 2018. The annual age-standardised PE-related mortality was consistently higher by up to 50% in Black individuals than in White individuals; these rates were approximately 50% higher in White individuals than in those of other races. In Canada, the annual age-standardised mortality rate from PE as the underlying cause of death decreased from 4·7 deaths per 100 000 population (4·4-5·0) in 2000 to 2·6 deaths per 100 000 population (2·4-2·8) in 2017; this decline slowed after 2006 across age groups and sexes.

Interpretation: After 2006, the initially decreasing PE-related mortality rates in North America progressively reached a plateau in Canada, while a rebound increase was observed among young and middle-aged adults in the USA. These findings parallel recent upward trends in mortality from other cardiovascular diseases and might reflect increasing inequalities in the exposure to risk factors and access to health care.

Funding: None.
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http://dx.doi.org/10.1016/S2213-2600(20)30417-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550106PMC
January 2021
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