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Background and Aims: Pulmonary embolism (PE) is a frequent complication in COVID19 hospitalized patients. Inflammatory storm and endothelial dysfunction due to the virus seem to be the two major risk factors for PE. Consequently, PE related to COVID19 could be consider as triggered by a transient inflammatory acute phase and treated for no longer than 3 months. However, few data are available on management of anticoagulation and risk of venous thromboembolic (VTE) recurrences in these patients and guidelines are still undefined. Aim of the present study is to evaluate the long-term follow-up of a cohort of covid-19 patients with PE., Methods: We conducted a retrospective multicenter study in four Italian hospitals between March 1st, 2020, and May 31st, 2021 in patients who experienced a PE during hospitalization for a COVID-19 pneumonia, excluding patients who died during hospitalization. Baseline characteristics were collected and patients were grouped according to duration of anticoagulant treatment (< 3 months or > 3 months). The primary outcome was incidence of VTE recurrence while secondary outcome was the composite of deaths, major hemorrhages and VTE recurrence during follow-up., Results: 106 patients with PE were discharged, of these 95 (89.6 %) had follow up longer than 3 months (seven patients were lost to follow up and four died within three months). The median follow-up was 13 months (IQR 1-19). Overall, 23 % of subjects (22/95) were treated for 3 months or less and 76.8 % (73/95) received anticoagulation for >3 months. Of patients in the short treatment group, 4.5 % died, compared with 5.5 % of those in the longer treatment group (p = NS); no difference was shown in risk of VTE recurrence (0 % vs 4.1 %, p = NS), major bleeding (4.5 % vs 4.1 %, p = NS) or in composite outcome (9.1 % vs 11 %, p = NS). No difference was found between the two treatment groups for composite outcome using the Kaplan-Meier analysis (Log Rank Test p = 0.387)., Conclusion: In our retrospective multi-center cohort, prolongation of duration of anticoagulation seems not to affect risk of VTE recurrences, deaths and bleeding after a PE related to COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Sacubitril/valsartan, the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitors (ARNIs), has been shown to reduce cardiovascular mortality and morbidity compared to enalapril in outpatient subjects with chronic heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, there is little real-world evidence about the efficacy of ARNIs in elderly hypertensive patients with HFrEF and comorbidities., Methods: In this prospective open-label study, 108 subjects, 54 of them (mean age 78.6 ± 8.2 years, 75.0 % male), with HFrEF (29.8 ± 4.3 %) and New York Heart Association (NYHA) class II-III symptoms were assigned to receive ARNIs twice daily, according to the recommended dosage of 24/26, 49/51, 97/103 mg. Patients were gender- and age-matched with a control arm of patients with HFrEF receiving the optimal standard therapy for HF. The clinic blood pressure (BP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), blood glucose and glycated hemoglobin (HbA1c), uric acid (UA), left ventricular ejection fraction (LVEF) and NYHA class were evaluated at a mean follow-up of 12 months. During the follow-up, the clinical outcomes, including mortality and re-hospitalization for HF, were collected., Results: NYHA class significantly improved in the ARNI arm compared to the control (24.9 vs. 6.4 %, shifting from class III to II, and 55.4 vs. 25.2 %, from class II to I, p < 0.05 for all). A significant improvement in LVEF and eGFR levels was found in the ARNI arm compared to controls (42.4 vs. 34.2 %, 73.8 vs. 61.2 mL/min, respectively; p < 0.001 for all). NT-proBNP, clinic systolic and diastolic BP, blood glucose, HbA1c and UA values were reduced in both treatment arms, but they were lower in the ARNI arm compared controls (3107 vs. 4552 pg/mL, 112.2 vs. 120.4 and 68.8 vs. 75.6 mmHg, 108.4 vs. 112.6 mg/dL, 5.4 vs. 5.9 % and 5.9 vs. 6.4 mg/dL, respectively, p < 0.05). Mortality and re-hospitalization for HF was lower in the ARNI arm than controls (20.1 vs. 33.6 % and 27.7 vs. 46.3 % respectively; p < 0.05 for all). Gender differences were not found in either arm. No patients refused to continue the study, and no side effects to the ARNI treatment were observed., Conclusions: In elderly patients with HFrEF and comorbidities, ARNI treatment seems effective and safe. The improvement in LVEF and cardiac remodeling, BP, eGFR, serum glucose, UA and HbA1c could be the mechanisms by which ARNIs play their beneficial role on clinical outcomes. However, these results need to be confirmed in studies involving a greater number of subjects, and with a longer follow-up., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: An abnormal ankle-brachial pressure index (ABI) is a marker of the risk for increased total and cardiovascular (CV) mortality. However, it is not clear whether it is associated with an even worse prognosis in patients with previous CV events or with cancer mortality., Materials and Methods: Consecutive subjects undergoing ABI assessment for suspected peripheral artery disease or for stratification of CV risk in ten centers in the Veneto Region (northeast Italy), between 2011 and 2014 were enrolled. The ABI was expressed as normal ≥0.9 to ≤1.3, and abnormal <0.9 or >1.3. All-cause mortality and CV or cancer mortality and hospitalizations for CV disease were collected from administrative databases up to December 2018., Results: The study enrolled 1,177 patients. ABI was abnormal in 57.2%. Median follow-up was 61.6 months (53.4-70.1). All-cause, CV and cancer mortality were higher in patients with abnormal than normal ABI, with hazard ratios (HR) respectively 2.0 (95% CI 1.48-2.69), 1.98 (95% CI 1.24-3.17) and 1.85 (95% CI 1.09-3.15). Among subjects with abnormal ABI, the risk of overall mortality, HR 1.57 (95% CI 1.17-2.12), and CV mortality, HR 2.39 (95% CI 1.43-3.99), was higher in those with previous CV events. These latter also had a higher risk of hospitalization for myocardial infarction and stroke: HR 1.85 (95% CI 1.023.37) and 2.17 (95% CI 1.10-4.28)., Conclusions: The co-existence of abnormal ABI and a history of CV events identifies subjects at higher risk, who call for a more aggressive approach. Abnormal ABI is also a predictor of cancer mortality., (Copyright © 2020. Published by Elsevier B.V.)

Background: The optimal long-term strategy for preventing recurrent venous thromboembolism (VTE) in patients with deep-vein thrombosis (DVT) is uncertain., Methods: In 620 consecutive outpatients with a first proximal DVT who had completed at least three months of anticoagulation (unprovoked in 483, associated with minor risk factors in 137), the ultrasound presence of residual vein thrombosis (RVT) was assessed and defined as an incompressibility of at least 4mm. In 517 patients without RVT and with negative D-dimer, anticoagulation was stopped and D-dimer was repeated after one and three months. Anticoagulation was resumed in 63 of the 72 patients in whom D-dimer reverted to positivity., Results: During a mean follow-up of three years, recurrent VTE developed in 40 (7.7%) of the 517 patients, leading to an annual rate of 3.6% (95% CI, 2.6 to 4.9): 4.1% (95% CI, 2.9 to 5.7) in individuals with unprovoked DVT, and 2.2% (95% CI, 1.1 to 4.5) in those with DVT associated with minor risk factors. Of the 233 males with unprovoked DVT, 17 (7.3%) developed events in the first year of follow-up. Major bleeding complications occurred in 8 patients while on anticoagulation, leading to an annual rate of 1.2% (95% CI, 0.6 to 2.4)., Conclusions: Discontinuing anticoagulation in patients with a first episode of proximal DVT based on the assessment of RVT and serial D-dimer leads to an overall annual rate of recurrent VTE lower than 5.0%, which is the rate deemed as acceptable by the Subcommittee on Control of Anticoagulation of the ISTH. However, in males with unprovoked DVT there is room for further improving the long-term strategy of VTE prevention. (ClinicalTrials.gov number, NCT01285661)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown., Methods: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins., Results: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months., Conclusions: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Although the role of homocysteinemia (Hcy) as a coronary risk factor (RF) has been scaled down, hyper-Hcy and carotid vascular damage (CVD) are still considered as RFs for cerebrovascular events. In 276 grade-1 hypertensives (160 men and 116 women aged 59.6 ± 15.0 years) without known cardiovascular disease and having hyper-Hcy (≥15 μM/L), subclinical CVD was evaluated by ultrasonographic carotid-wall intima media thickness (IMT). Hcy was divided into quartiles and C667→T polymorphism codifying for methylenetetrahydrofolate reductase (MTHFR) was determined. According to the genotype, subjects were divided into CC (wild), CT (heterozygote) and TT (homozygous mutation). Differences between continuous variables were evaluated by analysis of variance, while gender specific odds ratio (OR) and 95 % confidence intervals (CI) of CVD (IMT >0.9 mm or plaque) were calculated by multivariate logistic regression analysis. Blood pressure (BP) values were not different across the quartiles of Hcy. In 46.4 % of cases, sub-clinical CVD was found, with a prevalence increasingly distributed in the quartiles of Hcy (31.9, 42, 52.2, 59.4 %, p < 0.001). Prevalence of TT allele of the MTHFR genotype was also significantly distributed in the quartiles of Hcy (13.6, 12.3, 23.5 and 50.6 %, p < 0.0001), whereas no relationship was found between genotype and CVD. The last quartile of Hcy predicted CVD (OR 1.32, CI 1.12-2.2, p = 0.02) independent of age (OR 1.23, CI 1.002-1.56, p = 0.0001), systolic BP (OR 1.52, CI 1.24-2.10), diabetes (OR 2.11, CI 1:32-2.88, p = 0.01) and smoking (OR 1.45, CI 1.14-1.98, p = 0.04). Adding gender did not modify the model. In hypertensives, Hcy values >36.5 μM/L independently predict CVD and in those who are also diabetic and smokers, Hcy assessment without MTHFR genotype should be recommended to obtain a better stratification of global cerebrovascular risk.

Background: Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage., Objective: To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment., Patients/methods: We carried out a multicenter, investigator-initiated, prospective cohort study. Patients at risk of VTE with a creatinine clearance between 20 and 50 mL min(-1) were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. The primary outcome was the incidence of major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB) and symptomatic VTE., Results: We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL min(-1) , and a mean Charlson co-morbidity index of 8.2. One patient had major bleeding (0.49%, 95% confidence interval [CI] 0.03-3.10), eight had CRNMB (3.88%, 95% CI 1.81-7.78) and three developed symptomatic VTE (1.46%, 0.38-4.55). Twenty-three patients (11.17%, 7.36-16.48) died. No independent predictors of bleeding were found at univariate analysis., Conclusions: The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk of both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients., (© 2012 International Society on Thrombosis and Haemostasis.)

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

Arterial hypertension (HT) is age dependent and, with the prolongation of life expectancy, affects more and more elderly people. In the elderly, HT is a risk factor for organ damage and cardiovascular (CV) events. Both pharmacologic and nonpharmacologic reduction of blood pressure (BP) is associated with a corresponding decrease in systolic-diastolic or isolated systolic HT. Clinical trials have shown that BP lowering is associated with a decrease in stroke and other CV events. Therefore, BP reduction per se appears more important than a particular class of antihypertensive drugs. The benefit of antihypertensive treatment has been confirmed up to the age of 80 years, remaining unclear in the octogenarians. The benefit in lowering diastolic BP between 80 and 90 mmHg is well established, while that of lowering systolic BP below 140 mmHg requires further confirmations.

Background: The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain., Objective: To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT., Design: Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not., Setting: 9 university or hospital centers in Italy., Patients: 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation., Intervention: Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial., Measurements: The rate of confirmed recurrent VTE during 33 months of follow-up., Results: Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67)., Limitations: The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded., Conclusion: Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT., Primary Funding Source: None.

Context: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies., Objective: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities., Design, Setting, and Patients: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007., Main Outcome Measure: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup., Results: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%)., Conclusion: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities., Trial Registration: clinicaltrials.gov Identifier: NCT00353093.

Endocrine arterial hypertension (EAH) a condition in which hormone excess results in clinically significant hypertension is a rare cause of hypertension. However in the last years its prevalence has increased, mostly due to the improvement of diagnostic work-up. In clinical practice, hypertensive subjects with suspicion of EAH currently undergo hormonal screening of the renin-aldosterone and catecholamines and glucocorticoids excess. This paper reviews current understanding for earlier recognition of the main forms of EAH and discusses screening laboratory methods and localization techniques that have enhanced the clinician's ability to make the diagnosis of EAH. Primary aldosteronism (PA) has recently been recognised as the most frequent cause of EAH. The aldosterone to renin ratio (ARR) is a highly recommended screening test for PA. When ARR is increased, confirmatory tests as saline infusion or fludrocortisone suppression are required. Differential diagnosis of PA requires adrenal gland imaging by computed tomography (CT) or magnetic resonance imaging (MRI), biochemical testing of the aldosterone response to posture, and selective adrenal venous sampling to differentiate unilateral aldosterone-producing adenoma from bilateral hyperplasia. Hypertension is frequently found in endogenous Cushing's Syndrome (CS). Twenty-four-hour urinary free cortisol measurement is the gold standard for the diagnosis of CS, but it must be confirmed by the overnight dexamethasone suppression test. CT and MRI are the primary imaging studies to perform, while scintigraphy is a useful confirmatory method. The most specific and sensitive diagnostic test for catecholamine-producing neoplasms is determination of urinary metanephrine levels; the neoplasms can be located by CT, MRI and metaiodo-benzylguanidine scintigraphy.