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

Background. 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. Methods and results. 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 (p = 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 (p = 0.29). One COVID-19 patient died due to COVID-19-related complications 14 days after acute PE. No major bleeding events occurred. Conclusions. 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

Mortality rate related to peripheral arterial disease: A retrospective analysis of epidemiological data (years 2008-2019).

BACKGROUND AND AIMS Peripheral arterial disease (PAD) is one of the most prevalent cardiovascular diseases with more than 230 million people being affected worldwide. As highlighted by the recent European Society of Cardiology guidelines, data on the epidemiology of PAD is urgently needed. METHODS AND RESULTS We accessed the vital registration data of the Veneto region (Northern Italy, approximately five millions inhabitants) covering the period 2008-2019. We computed annual age-standardized rates for PAD reported as the underlying cause of death (UCOD) or as one of multiple causes of death (MCOD). Age-adjusted odds ratios (OR) served to study the association between PAD and cardiovascular comorbidities. The age-standardized mortality rate for PAD as MCOD slightly declined from 19.6 to 17.8 in men and from 10.8 to 9.1 deaths per 100,000 population-years in women. The age-standardized PAD-specific mortality rate (UCOD) remained stable: 3.1 to 3.7 per 100,000 person-years in women (Average Annual Percent Change 1.3, 95% CI -0.8; 3.4%) and 4.4 to 4.3 per 100,000 person-years (Average Annual Percent Change -0.2, 95% CI -3.6; 3.4%) in men. PAD contributed to 1.6% of all deaths recorded in the region. Ischemic heart disease, diabetes mellitus and neoplasms were the most prevalent UCOD among PAD patients. PAD was associated with diabetes mellitus (OR 3.79, 95%CI 3.55-4.06) and chronic kidney diseases (OR 2.73, 95%CI 2.51-2.97) in men, and with atrial fibrillation (OR 2.26, 95%CI 2.10-2.44) in women. CONCLUSION PAD remains a substantial cause of death in the general population of this high-income region of Western Europe with marked sex-specific differences

Clinical outcomes of ultrasound-assisted coagulation monitoring-adjusted catheter-directed thrombolysis for acute pulmonary embolism

BACKGROUND Ultrasound-assisted catheter-directed thrombolysis (USAT) may reverse right ventricular dysfunction due to acute pulmonary embolism (PE) with a favorable safety profile. METHODS We studied intermediate-high- and high-risk acute PE patients who underwent USAT at the University Hospital Zurich, 2018-2022. The USAT regimen included alteplase 10 mg per catheter over 15 h, therapeutic-dosed heparin, and dosage adaptations based on routinely monitored coagulation parameters, notably anti-factor Xa activity and fibrinogen. We focused on the mean pulmonary arterial pressure (mPAP) and the National Early Warning Score (NEWS) before and after USAT, and reported the incidence of hemodynamic decompensation, PE recurrence, major bleeding, and death over 30 days. RESULTS We included 161 patients: 96 (59.6 %) were men and the mean age was 67.8 (SD 14.6) years. Mean PAP decreased from a mean of 35.6 (SD 9.8) to 25.6 (SD 8.2) mmHg, whereas the NEWS decreased from a median of 5 (Q1-Q3 4-6) to 3 (Q1-Q3 2-4) points. No cases of hemodynamic decompensation occurred. One (0.6 %) patient had an episode of recurrent PE. Two (1.2 %) major bleeding events occurred, including one (0.6 %) intracranial, fatal hemorrhage in a patient with high-risk PE, severe heparin overdosing, and a recent head trauma (with negative CT scan of the brain performed at baseline). No other deaths occurred. CONCLUSIONS USAT resulted in a rapid improvement of hemodynamic parameters among patients with intermediate-high risk acute PE and selected ones with high-risk acute PE, without any recorded deaths related to PE itself. A strategy including USAT, therapeutic-dosed heparin, and routinely monitored coagulation parameters may partly explain the overall very low rate of major bleeding

Coagulation-monitored, dose-adjusted catheter-directed thrombolysis or pharmaco-mechanical thrombus removal in deep vein thrombosis

Background: Pharmaco-mechanical thrombectomy (PMT) and catheter-directed thrombolysis (CDT) are therapeutic options for selected patients with acute deep vein thrombosis (DVT) to prevent post-thrombotic syndrome (PTS). Patients and methods: We aimed to describe the clinical characteristics and outcomes of 159 patients with symptomatic iliofemoral DVT undergoing PMT alone, CDT alone, or CDT followed by PMT (bail-out) in the Swiss Venous Stent Registry. The primary outcome was the incidence of peri-interventional major and minor bleeding complications (ISTH criteria). Secondary outcomes included the incidence of PTS and stent patency after 3 years. Results: Mean age was 49±20 years and 58% were women. DVT involved the iliac veins in 99% of patients, whereas 53% had an underlying iliac vein compression. PMT alone was used in 40 patients, CDT alone in 77, and 42 received initial CDT followed by bail-out PMT due to insufficient thrombus clearance. Single-session PMT was the preferred approach in patients with iliac vein compression, patent popliteal vein, and absence of IVC thrombus. Patients treated with PMT alone received a lower r-tPA dose (median 10 mg, IQR 10-10) vs. those treated with CDT (20 mg, IQR 10-30). The rate of peri-interventional major bleeding was 0%, 1%, and 2%, whereas that of minor bleeding was 0%, 1%, and 12%, respectively, all occurring during CDT. After 3 years, PTS occurred in 6%, 9%, and 7% of patients, respectively. The primary stent patency rate was 95%, 88%, and 83%, respectively. Conclusions: The use of PMT and CDT for iliofemoral DVT was overall safe and resulted in high long-term patency and treatment success. Given the less severe presentation of DVT, single-session PMT appeared to be characterized by numerically better primary patency and lower perioperative bleeding event rates than CDT

Common laboratory tests and their correlation with the clinical presentation and prognosis of lemierre syndrome

INTRODUCTION Lemierre syndrome is a thromboembolic complication following an acute bacterial infection of the head/neck area, often due to anaerobes. Data on the prognostic role of laboratory parameters is lacking. METHODS We analyzed individual-patient level data from a multinational cohort of patients with Lemierre-syndrome. Patients had an infection in the head/neck area, and contiguous vein thrombosis or septic embolism, irrespective of the causal pathogen. We studied the patterns of white blood cell count, platelet count, and C-reactive protein concentration investigating their association with baseline characteristics and in-hospital clinical outcomes (septic embolism, major bleeding, all-cause death). RESULTS A total of 447 (63%) patients had complete data for analysis. White blood cells were elevated across all subgroups (median 17 × 10$^{3}$/μL; Q1-Q3:12-21). Median platelet count was 61 × 10$^{3}$/μL (Q1-Q3:30-108) with decreasing levels with increasing age. Males, patients with renal failure or cardiopulmonary impairment, and those with typical Lemierre syndrome (tonsillitis, septic thromboembolism, positivity for Fusobacterium spp.) had the lowest platelet count. Median C-reactive protein was 122 (Q1-Q3:27-248) mg/L with higher values in patients who also had more severe thrombocytopenia. The overall risk of complications was similar across subgroups of patients stratified according to white blood cell and C-reactive protein levels. Patients in the lowest third of platelet count (<42 × 10$^{3}$/μL) had the highest rate of complications (26%), as opposed to those in the highest third (11%), notably septic embolic events. CONCLUSIONS Common laboratory tests correlate with the clinical presentation of Lemierre syndrome. However, extreme values did not appear to be prognostically relevant for in-hospital complications and potentially able to improve clinical management

Differences in duration of anticoagulation after pulmonary embolism and deep vein thrombosis: Findings from the SWIss Venous ThromboEmbolism Registry (SWIVTER).

BACKGROUND Although the two manifestations of venous thromboembolism (VTE), deep vein thrombosis (DVT) and pulmonary embolism (PE), vary considerably, the consensus guidelines recommend similar algorithms for therapeutic anticoagulation in both conditions. Real-world data assessing contemporary management strategies in PE and DVT alone may help tailoring future recommendations towards more individualized patient care. METHODS In the present analysis, we compared demographics, comorbidities, treatment patterns, and clinical outcomes of PE versus DVT only among 2062 consecutive patients with confirmed VTE enrolled by 11 acute care hospitals between November 2012 and February 2015 in the SWIss Venous ThromboEmbolism Registry (SWIVTER). RESULTS Overall, 1246 (60 %) patients were diagnosed with PE. In comparison to DVT alone, PE patients were older (66 vs. 59 years; p < 0.001), more frequently had acute and chronic comorbidities, less frequently had prior VTE and hormone replacement, and were less often pregnant. VTE was considered similarly often provoked in patients with PE and DVT alone (33.8 % vs. 33.5 %; p = 0.88). Anticoagulation for an indefinite duration was more often prescribed to patients with PE than those with DVT alone (45.7 vs. 19.6 %; p < 0.001), and PE diagnosis was the strongest independent predictor of indefinite anticoagulation (OR 3.21; 95 % CI 2.55-4.06; p < 0.001). Diagnosis of PE was associated with both increased risk of 90-day mortality (HR 2.31, 95 % CI 1.44-3.71; p = 0.001) and major bleeding (HR 3.88, 95 % CI 1.63-9.22; p = 0.002). CONCLUSIONS Our analysis affirms differences in demographics, risk factors, and clinical outcomes of PE versus DVT alone. In routine clinical practice, duration of anticoagulation is being managed differently between the two manifestations of VTE, in contrast to recommendations of the current consensus guidelines

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

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

Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial

INTRODUCTION The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. METHODS Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. RESULTS Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. CONCLUSIONS In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms

Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial.

INTRODUCTION The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. METHODS Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. RESULTS Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. CONCLUSIONS In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms

Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial

INTRODUCTION: The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. METHODS: Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. RESULTS: Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. CONCLUSIONS: In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms