Prevalence of Pulmonary Embolism among Patients Hospitalized for Syncope.

BACKGROUND: The prevalence of pulmonary embolism among patients hospitalized for syncope is not well documented, and current guidelines pay little attention to a diagnostic workup for pulmonary embolism in these patients. METHODS: We performed a systematic workup for pulmonary embolism in patients admitted to 11 hospitals in Italy for a first episode of syncope, regardless of whether there were alternative explanations for the syncope. The diagnosis of pulmonary embolism was ruled out in patients who had a low pretest clinical probability, which was defined according to the Wells score, in combination with a negative d-dimer assay. In all other patients, computed tomographic pulmonary angiography or ventilation-perfusion lung scanning was performed. RESULTS: A total of 560 patients (mean age, 76 years) were included in the study. A diagnosis of pulmonary embolism was ruled out in 330 of the 560 patients (58.9%) on the basis of the combination of a low pretest clinical probability of pulmonary embolism and negative d-dimer assay. Among the remaining 230 patients, pulmonary embolism was identified in 97 (42.2%). In the entire cohort, the prevalence of pulmonary embolism was 17.3% (95% confidence interval, 14.2 to 20.5). Evidence of an embolus in a main pulmonary or lobar artery or evidence of perfusion defects larger than 25% of the total area of both lungs was found in 61 patients. Pulmonary embolism was identified in 45 of the 355 patients (12.7%) who had an alternative explanation for syncope and in 52 of the 205 patients (25.4%) who did not. CONCLUSIONS: Pulmonary embolism was identified in nearly one of every six patients hospitalized for a first episode of syncope. (Funded by the University of Padua; PESIT ClinicalTrials.gov number, NCT01797289 .).

Scoring Systems for Estimating Risk of Venous Thromboembolism in Hospitalized Medical Patients.

Deep vein thrombosis and pulmonary embolism are associated with considerable morbidity and mortality in hospitalized patients, accounting for up to 10% of hospitalization-related deaths in both surgical and medical patients. Pharmacologic thromboprophylaxis has been demonstrated to be effective, safe, and cost-effective in preventing hospital-acquired venous thromboembolism (VTE) among medical inpatients, and clinician awareness of thrombotic risk promotes prescription of thromboprophylaxis. Guidelines recommend stratification of thrombotic risk for all patients and, unless contraindicated, administration of VTE prophylaxis. Based on several recognized predisposing and exposing risk factors for VTE, several scoring systems have been published in the past 15 years. Borrowing models developed in the surgical setting, recognized risk factors for VTE complications in medical inpatients have been combined in different weighted scores and derived and validated in heterogeneous medical populations. Although the perfect score, balancing thrombotic and hemorrhagic risk, has probably not yet been built, the adoption of an easy-to-use risk assessment model has the potential to support physicians in properly stratifying VTE risk in medical inpatients, tailoring thromboprophylaxis prescription.

Incidence of arterial embolism in patients on treatment with old and new anticoagulants for venous thromboembolism.

The separate nature of venous and arterial thrombotic disorders has recently been challenged. Patients with venous thromboembolism (VTE) have an increased risk of subsequent symptomatic arterial cardiovascular events, the risk being higher in those with unexplained episodes. Among the implications of this association, there is the potential for old and new antithrombotic drugs to impact on the development of both venous and arterial cardiovascular events. According to the results of recent studies, aspirin in low doses, when administered for the long-term management of patients with unprovoked VTE, reduces by approximately 35% the risk of recurrent VTE while offering a considerable protection against the development of arterial cardiovascular events. By contrast, there is no room to expect a reduction in the risk of subsequent arterial cardiovascular events in patients treated with vitamin K antagonists (VKA) in comparison to patients in whom VKAs are discontinued. According to the results from recent randomized clinical trials, the likelihood of arterial cardiovascular events in patients on the novel direct factor Xa inhibitors is unlikely to differ from that of patients receiving conventional anticoagulation. As dabigatran has been associated with a slight increase in the risk of myocardial infarction over warfarin, its use should be discouraged in patients with coronary heart disease. The long-term use of low-dose apixaban beyond the first months in patients with unprovoked VTE may decrease the long-term risk of arterial, as well as venous, thrombotic events.

Risk factors, antithrombotic treatment and outcome in retinal vein occlusion: an age-related prospective cohort study.

OBJECTIVES: Antithrombotic treatment for retinal vein occlusion (RVO) is controversial, although RVO has been surmised as a predictor of a subsequent vascular event. We aimed to evaluate risk factors, the effects of antithrombotic therapy and the occurrence of subsequent vascular events in patients with a first episode of RVO, according to age of RVO onset. METHODS: In this prospective cohort study, patients with central (CRVO) and branch RVO (BRVO) confirmed by fluorescein angiography were studied; they were divided according to age. Cardiovascular risk factors and thrombophilia were evaluated. Anticoagulants or aspirin were given for at least 3 months. Patients were followed every 6-12 months and vascular events were recorded. RESULTS: One hundred CRVO and 32 BRVO patients were enrolled. Five of 60 (8.3%) patients <50 yr and 4/72 (5.5%) over 50 yr had a hereditary thrombophilic defect. One or more cardiovascular risk factors were found in 35 (58%) patients of the younger group, and in 66 (91%) of the older group (P < 0.001). Antithrombotic treatment led to both a satisfactory recanalization of occluded veins and visual acuity improvement especially in younger patients. Vascular events occurred in 19 (14%) cases after 4 ± 3.3 yr from RVO, more frequently in older than in younger patients (22% vs. 5%, P = 0.005). CONCLUSIONS: Distribution of cardiovascular, but not of thrombophilic risk factors seems to be influenced by age in RVO patients. Patients with a first RVO, especially those >50 yr, are likely at risk of a subsequent vascular event.

Long term follow-up of a multicentre cohort of COVID-19 patients with pulmonary embolism: Anticoagulation management and outcomes.

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.

A prospective cohort study on patients treated with anticoagulants for cerebral vein thrombosis.

OBJECTIVES: Cerebral vein thrombosis (CVT) is a potentially fatal disorder for which treatment guidelines are scanty. To assess the short- and long-term benefit of anticoagulant therapy, we performed a prospective cohort study on CVT patients. METHODS: Forty-four consecutive CVT patients received conventional anticoagulation with heparin followed by warfarin for at least 3 months. Patients presenting with symptoms suggestive of pulmonary embolism (PE) underwent confirmatory objective tests. Acquired or inherited risk factors for thrombosis were investigated in all patients. Thrombotic and hemorrhagic events occurring during treatment, and the long-term outcome using the modified Rankin Scale (mRS) were recorded. RESULTS: Congenital and/or acquired conditions predisposing to thrombosis were detected in 37 patients (84.1%), with a high prevalence of oral contraceptive use (66.7% of females) and thrombophilia (31.8%); more than one risk factor was seen in 31.8% of cases. At referral, six patients (13.6%) presented with symptoms of PE, which was confirmed in all. During the initial treatment period, two patients (4.5%) developed symptomatic progression of CVT, which was fatal in 1, and 2 (4.5%) developed major bleeding complications. A favorable outcome (mRS 0-2) at 6-12 months was recorded in 37 of the 43 patients who survived the acute phase (86%). CONCLUSIONS: The outcome of CVT patients managed with conventional anticoagulation who survive the initial phase is favorable in the vast majority. The prevalence of concomitant PE is considerably high, supporting the need of anticoagulant therapy.

Predicting in-Hospital Mortality of Patients with COVID-19 Using Machine Learning Techniques.

The present work aims to identify the predictors of COVID-19 in-hospital mortality testing a set of Machine Learning Techniques (MLTs), comparing their ability to predict the outcome of interest. The model with the best performance will be used to identify in-hospital mortality predictors and to build an in-hospital mortality prediction tool. The study involved patients with COVID-19, proved by PCR test, admitted to the "Ospedali Riuniti Padova Sud" COVID-19 referral center in the Veneto region, Italy. The algorithms considered were the Recursive Partition Tree (RPART), the Support Vector Machine (SVM), the Gradient Boosting Machine (GBM), and Random Forest. The resampled performances were reported for each MLT, considering the sensitivity, specificity, and the Receiving Operative Characteristic (ROC) curve measures. The study enrolled 341 patients. The median age was 74 years, and the male gender was the most prevalent. The Random Forest algorithm outperformed the other MLTs in predicting in-hospital mortality, with a ROC of 0.84 (95% C.I. 0.78-0.9). Age, together with vital signs (oxygen saturation and the quick SOFA) and lab parameters (creatinine, AST, lymphocytes, platelets, and hemoglobin), were found to be the strongest predictors of in-hospital mortality. The present work provides insights for the prediction of in-hospital mortality of COVID-19 patients using a machine-learning algorithm.

External validation of the simplified Geneva risk assessment model for hospital-associated venous thromboembolism in the Padua cohort.

BACKGROUND: The simplified Geneva risk assessment model (RAM) predicts the risk of hospitalization-related venous thromboembolism (VTE) in medical inpatients in its developmental cohort but has not been validated. OBJECTIVES: To externally validate the simplified Geneva RAM. PATIENTS/METHODS: For this secondary analysis of a prospective cohort set in Padua, we calculated the simplified Geneva RAM for all participants. They were followed up for 90 days for the occurrence of adjudicated VTE. Thirty- and 90-day risks of VTE were estimated by the Kaplan-Meier method, and categories of risks compared with a Cox regression model adjusted for the use of thromboprophylaxis. RESULTS: Among 1180 medical inpatients, the 90-day risk of symptomatic VTE was 3.1%. The simplified Geneva RAM classified 56.9% as high risk (≥3 points; 90-day risk of VTE of 5.2%) and 43.1% as low risk (<3 points; 90-day risk of VTE of 0.4%). Compared with low-risk participants, high-risk participants had an 18-fold greater risk of VTE than low-risk participants (hazard ratio [HR] 17.9, 95% confidence interval [CI] 4.3-74.7). A very high-risk category (≥7 points) identified 5.3% of participants with a 9.5% probability of VTE at 90 days. CONCLUSIONS: In this external validation study, we confirm the excellent discrimination and clinically adequate calibration of the simplified Geneva RAM as a stratification tool to guide the use of thromboprophylaxis.

A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism.

BACKGROUND: The Bova score has shown usefulness in the identification of intermediate-high risk patients with acute pulmonary embolism (PE), but lacks prospective validation. The aim of this study was to prospectively validate the Bova score in different settings from the original derivation cohort. METHODS: Consecutive, normotensive patients with acute PE recruited at 13 academic or general hospitals were stratified, using their baseline data, into the three Bova risk stages (I-III). The primary outcome was the 30-day composite of PE-related mortality, hemodynamic collapse and non-fatal PE recurrences in the three risk categories. RESULTS: In the study period, 639 patients were enrolled. The primary end point occurred in 45 patients (7.0%; 95% Confidence Intervals, 5.2%-9.3%). Risk stage correlated with the PE-related complication rate (stage I, 2.9%; stage II, 17%; stage III, 27%). Patients classified as stage III by the Bova score had a 6.5-fold increased risk for adverse outcomes (3.1-13.5, p < 0.001) compared with stages I and II combined. Rescue thrombolysis increased from stage I to stage III (0.6%, 12% and 15% respectively). All-cause mortality (5.3%) did not substantially differ among the stages. CONCLUSIONS: The Bova score accurately stratifies normotensive patients with acute PE into stages of increasing risk of 30-day PE-related complications.

Optimal duration of anticoagulation. Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests.

Once anticoagulation is stopped, the risk of recurrent venous thromboembolism (VTE) over years after a first episode is consistently around 30%. This risk is higher in patients with unprovoked than in those with (transient) provoked VTE, and among the latter in patients with medical than in those with surgical risk factors. Baseline parameters that have been found to be related to the risk of recurrent VTE are the proximal location of deep-vein thrombosis, obesity, old age, male sex and non-0 blood group, whereas the role of inherited thrombophilia is controversial. The persistence of residual vein thrombosis at ultrasound assessment has consistently been shown to increase the risk, as do persistently high values of D-dimer and the early development of the post-thrombotic syndrome. Although the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, strategies that incorporate the assessment of residual vein thrombosis and D-dimer have the potential to identify subjects in whom anticoagulation can be safely discontinued. Moreover, new opportunities are offered by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving the same effectiveness; and by low-dose aspirin, which has the potential to prevent the occurrence of both venous and arterial thrombotic events.

The risk of recurrent thromboembolic disorders in patients with unprovoked venous thromboembolism: new scenarios and opportunities.

The risk of recurrent thromboembolic disorders in the 10-year period following an episode of unprovoked venous thromboembolism (VTE) ranges between 30 and 50%, the rate being higher in patients with primary deep venous thrombosis (DVT) than in those with primary pulmonary embolism (PE). The clinical presentation with primary PE increases by more than three times the risk of a new PE episode over that with isolated DVT. Baseline parameters that increase this risk are the proximal location of DVT, obesity, old age and male sex, whereas the role of thrombophilia is controversial. An increasing role is played by post-baseline parameters such as the ultrasound assessment of residual vein thrombosis and the determination of D-dimer. While the latest international guidelines suggest indefinite anticoagulation for most patients with the first episode of unprovoked VTE, new scenarios are being offered by the identification of risk stratification models and by strategies that have the potential to help identify patients in whom anticoagulation can be safely discontinued, such as those that incorporate the assessment of D-dimer and residual vein thrombosis. New opportunities are being offered by low-dose aspirin, which has recently been reported to decrease by more than 30% the risk of recurrent events without increasing the bleeding risk; and especially by a few emerging anti-Xa and anti-IIa oral compounds, which are likely to induce fewer haemorrhagic complications than vitamin K antagonists while preserving at least the same effectiveness, do not require laboratory monitoring, and can be used immediately after the thrombotic episode.

The value of inhibitors of factor Xa for the treatment of pulmonary embolism.

The introduction of factor Xa inhibitors advocated the initiation of clinical trials that addressed the value of anticoagulation in patients with hemodynamically stable primary pulmonary embolism (PE). In the Matisse trial in patients with PE, fondaparinux administered at therapeutic doses followed by vitamin K antagonists (VKA) has shown a comparable efficacy and safety profile to that seen with intravenous adjusted-dose unfractionated heparin/VKA. A long-acting derivative of fondaparinux, idraparinux, failed to achieve similar results. On the other hand, the Cassiopea study revealed that once weekly injections of idrabiotaparinux, a slightly modified form of idraparinux, have similar efficacy and better safety profile compared to VKAs in the long-term treatment of patients with PE. However, the inconvenient parenteral administration of both fondaparinux and idrabiotaparinux limits their routine clinical use. The availability of antithrombotic compounds that can be administered orally in fixed dose, owing to their predictable pharmacokinetics and pharmacodynamics, and have a lower potential for drug and food interactions has opened new horizons for the treatment of patients with PE. The Einstein PE, Amplify and Hokusai studies, conducted with rivaroxaban, apixaban and edoxaban, respectively, showed that for the treatment of PE they possess a more favorable benefit-to-risk profile than the conventional antithrombotic drugs. In addition, rivaroxaban and apixaban make it possible to treat uncomplicated PE patients from the beginning, without the need for the parenteral administration of heparins or fondaparinux, and edoxaban allows the treatment of fragile patients with lower doses. All of them cover a wide spectrum of clinical presentations, including PE patients at intermediate risk.

Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study.

BACKGROUND: Little information is available on the long-term clinical outcome of cerebral vein thrombosis (CVT). OBJECTIVES AND METHODS: In an international, retrospective cohort study, we assessed the long-term rates of mortality, residual disability and recurrent venous thromboembolism (VTE) in a cohort of patients with a first CVT episode. RESULTS: Seven hundred and six patients (73.7% females) with CVT were included. Patients were followed for a total of 3171 patient-years. Median follow-up was 40 months (range 6, 297 months). At the end of follow-up, 20 patients had died (2.8%). The outcome was generally good: 89.1% of patients had a complete recovery (modified Rankin Score [mRS] 0-1) and 3.8% had a partial recovery and were independent (mRS 2). Eighty-four per cent of patients were treated with oral anticoagulants and the mean treatment duration was 12 months. CVT recurred in 31 patients (4.4%), and 46 patients (6.5%) had a VTE in a different site, for an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% confidence Interval [CI] 17.8, 28.7) and of 35.1 events/1000 patient-years (95% CI, 27.7, 44.4) after anticoagulant therapy withdrawal. A previous VTE was the only significant predictor of recurrence at multivariate analysis (hazard ratio [HR] 2.70; 95% CI 1.25, 5.83). CONCLUSIONS: The long-term risk of mortality and recurrent VTE appears to be low in patients who survived the acute phase of CVT. A previous VTE history independently predicts recurrent events.

The risk of cancer progression in women with gynecological malignancies and thrombophilic polymorphisms: a pilot case-control study.

Cancer produces a hypercoagulable state, which might lead to thrombosis, and on contrary, unprovoked venous thromboembolism might be the manifestation of an occult cancer. In this pilot case-control study, we assessed the risk of gynecological malignant diseases related to the presence of the factor V Leiden and prothrombin G20210A polymorphisms. Fifty-two women underwent an operation for gynecological malignancy and were enrolled in the study. Women who underwent an operation for gynecological nonmalignant disease in the same days of cases were considered as controls. The presence of factor V Leiden and prothrombin G20210A was assessed in case and control groups. In all, 7 out of 52 cases were carriers of the 2 polymorphisms compared with 20 out of 198 controls (odds ratio = 1.3; 95% confidence interval, 0.6-3.0). The results were also similar when the risk was considered separately for the site of cancer. As for advanced and metastatic malignancies, the odds ratios were 2.3 (95% confidence interval, 0.9-6.0) and 3.3 (95% confidence interval, 1.0-11), respectively, compared to noncancer patients. When these 2 groups were compared to nonadvanced cancer group, the odds ratios for carriers of polymorphisms were 2.7 (95%confidence interval, 0.7-11.0) and 3.9 (95%confidence interval, 0.8-18.6) for advanced cancer and metastatic malignancies, respectively. Women with factor V Leiden or prothrombin G20210A polymorphisms who developed gynecological malignancy might present with a higher stage of cancer at the time of surgery. Larger case-control studies in similar cohort of patients are needed to confirm these findings.