The Use of Risk Scores for Thromboprophylaxis in Medically Ill Patients-Rationale and Design of the RICO trial.

Background Venous thromboembolism (VTE) in hospitalized medically ill patients is a significant cause of morbidity and mortality. Guidelines suggest that VTE and bleeding risk assessment models (RAMs) should be integrated into the clinical decision-making process on thromboprophylaxis. However, poor evidence is available comparing the use of a RAM versus clinical judgement in evaluating VTE and bleeding occurrence. Methods Reducing Important Clinical Outcomes in hospitalized medical ill patients (RICO) is a multicenter, cluster-randomized, controlled clinical trial (ClinicalTrials.gov Identifier: NCT04267718). Acutely ill patients hospitalized in Internal Medicine wards are randomized to the use of RAMs-namely the Padua Prediction Score and the International Medical Prevention Registry on Venous Thromboembolism Bleeding Score-or to clinical judgement. The primary study outcome is a composite of symptomatic objectively confirmed VTE and major bleeding at 90-day follow-up. Secondary endpoints include the evaluation of clinical outcomes at hospital discharge and the assessment of VTE prophylaxis prescription during the study period. In order to demonstrate a 50% reduction in the primary outcome in the experimental group and assuming an incidence of the primary outcome of 3.5% in the control group at 90-day; 2,844 patients across 32 centers will be included in the study. Discussion The RICO trial is a randomized study of clinical management assessing the role of RAMs in hospitalized medical ill patients with the aim of reducing VTE and bleeding occurrence. The study has the potential to improve clinical practice since VTE still represents an important cause of morbidity and mortality in this setting.

Intentional Rounding versus Standard of Care for Patients Hospitalised in Internal Medicine Wards: Results from a Cluster-Randomised Nation-Based Study.

The aim of the study was to explore the effects of Intentional Rounding, a regular-based proactive patient monitoring, on falls and pressure ulcers in internal medicine units. This is a cluster-randomised controlled study, where units were assigned (1:1) to Intentional Rounding (intervention group) or Standard of Care (control group). The primary outcome was the cumulative incidence of falls and new pressure ulcers. These events were considered separately as secondary endpoints, together with the number of bell calls and the evaluation of patient satisfaction. Primary analyses were carried out on the modified intention-to-treat population (hospitalisation of at least 10 days). Recruitment occurred between October 2019 and March 2020, at which time the study was prematurely closed due to the COVID-19 pandemic. Enrolment totalled 1822 patients at 26 sites; 779 patients were included in the modified intention-to-treat analysis. The intervention group had a lower risk of falls (adjusted incidence rate ratio 0.14; 95% confidence interval, 0.02-0.78; p = 0.03). There were no statistical differences in new pressure ulcers or the cumulative incidence of both adverse events. Mean bell calls for each patient were 15.4 ± 24.1 in the intervention group and 13.7 ± 20.5 in the control group (p = 0.38). Additionally, patient satisfaction in the intervention group was almost at the maximum level. Our study supports the usefulness of Intentional Rounding in a complex and vulnerable population such as that hospitalised in internal medicine units.

Correction: Di Micco et al. Clinical Differences between COVID-19 and a COVID-like Syndrome. J. Clin. Med. 2021, 10, 2519.

Incorrect Affiliation [...].

Hospitalization and mortality for acute exacerbation of asthma: an Italian population-based study.

Asthma is an ever-increasing disease with a highly variable prevalence among different ethnic groups. Information on hospital admission for acute exacerbation of asthma in adult patients and data regarding short-term prognosis of these patients are limited. We, thus, performed an epidemiological study on hospital admission for asthma acute exacerbation in Italy using hospital discharge database records derived from all Italian hospitals. Patients > 15 years old were identified using clinical Modification (ICD-9-CM) codes. Information on baseline characteristics, vital status at discharge, duration of hospitalization, and up to five secondary discharge diagnoses was collected. Comorbidity was evaluated using the Charlson comorbidity index (CCI). During the observation period (2013-2014), 20,056 patients with asthma acute exacerbation were hospitalized. Median length of hospitalization was 7.9 days (interquartile range 4-10) and mean in-hospital mortality was 0.8%. In-hospital mortality and length of hospitalization varied among different regions (from 0 to 2.9% and from 6.5 to 8.9 days, respectively). Old age, invasive and non-invasive mechanical ventilation, and CCI resulted as significantly associated with higher in-hospital mortality. Our study results, on a large sample of patients, confirm that hospitalization for asthma acute exacerbation is not uncommon among Italian current population. Older age, high CCI, and use of ventilator support were associated with a higher mortality rate. These findings should be analyzed to set up appropriate health care policies on patients with asthma.

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

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

Clinical Differences between COVID-19 and a COVID-Like Syndrome.

COVID-19 is an infection due to SARS-CoV-2; this virus has been identified as the cause of the present pandemic. Several typical characteristics are present in this infection, in particular pneumonia with possible lung failure, but atypical clinical presentations are being described daily by physicians around the world. Ground-glass opacities with pneumonia are the most common and dangerous presentations of the COVID-19 disease, and they are usually associated with positive nasopharyngeal swab (NPS) tests with detectable SARS-CoV-2 viral RNA. Compared to the general population, hospital workers have been at a greater risk of infection ever since the first patients were hospitalized. However, hospital workers have also been reported as having COVID-like symptoms despite repeated negative swab tests but having tested positive for SARS-CoV-2 antibodies with serological tests. We can postulate that a COVID-like syndrome is possible, in particular in hospital workers, that is characterized by symptoms similar to those of COVID-19, but with repeated negative nasopharyngeal swabs. These repeated negative NSPs make the difference in daily clinical management with people that experienced a single false negative nasopharyngeal swab; furthermore, a clear clinical differentiation of these situations is still lacking in the literature. For this reason, here, we report our main findings from a cohort of patients with a COVID-like syndrome compared to a similar group affected by typical COVID-19.

Antithrombotic and Anti-Inflammatory Effects of Fondaparinux and Enoxaparin in Hospitalized COVID-19 Patients: The FONDENOXAVID Study.

BACKGROUND: Since the outbreak of novel coronavirus SARS-CoV2 around the world, great attention has been paid to the effects of such antithrombotic drugs as heparinoids, because they have antiviral action in vitro and antithrombotic actions in vivo. We conducted a retrospective analysis in inpatients with confirmed COVID-19 on the anti-inflammatory and antithrombotic effects of enoxaparin and fondaparinux at prophylactic doses. METHODS: This retrospective cohort study used patients with confirmed COVID-19 during the first months of the Italian outbreak from February 18 to April 30, 2020. Our aim was to compare clinical characteristics, prophylactic treatment, markers of inflammation, and thrombotic outcomes in inpatients positive for SARS-CoV2 during hospitalization associated with thromboprophylaxis with enoxaparin (40 mg or 60 mg once daily) or fondaparinux (2.5 mg once daily). Statistical analysis was conducted with using MatLab R2016B and ad hoc functions. RESULTS: There were no significatant differences in clinical characteristics between patients that used enoxaparin or fondaparinux as thromboprophylaxis for SARS-CoV2. No differences were found in D-dimer and fibrinogen levels either, which were used as markers of inflammation during the infection at testing on admission and after 3 weeks.Significant differences in CRP, IL6, and LDH were found in patients after 21 days' treatment. DISCUSSION: Increased levels of fibrinogen and D-dimer in patients with confirmed COVID-19 have been reported in several studies. Our results showed that anti-inflammatory effects of fondaparinux and enoxaparin after 3 weeks of prophylactic treatment were similar when levels of fibrinogen and D-dimer were considered. Furthermore, levels of CRP showed a decrease in patients treated with enoxaparin and fondaparinux, although the decrease in the fondaparinux group seems to be more relevant.

Resolution of Disseminated Intravascular Coagulation in a Patient with COVID-19 and Associated Sepsis-Induced Neutropenia.

COVID-19 has been associated with a hypercoagulable state and thrombotic events. Venous thromboembolism has been the most commonly reported type of thrombosis but also arterial thrombosis and disseminated intravascular coagulation in inpatients have been described frequently in several clinical experiences. Patients with COVID-19, because of its tendency to induce leucopenia and overlapping of bacterial infection, may experience sudden disseminated intravascular coagulation (DIC), as in the case that we report here. However, early diagnosis and treatment may be associated with positive resolution of these severe complications.

Acute cardiovascular events in patients with community acquired pneumonia: results from the observational prospective FADOI-ICECAP study.

BACKGROUND: The burden of cardiovascular (CV) complications in patients hospitalised for community-acquired pneumonia (CAP) is still uncertain. Available studies used different designs and different criteria to define CV complications. We assessed the cumulative incidence of acute of CV complications during hospitalisation for CAP in Internal Medicine Units (IMUs). METHODS: This was a prospective study carried out in 26 IMUs, enrolling patients consecutively hospitalised for CAP. Defined CV complications were: newly diagnosed heart failure, acute coronary syndrome, new onset of supraventricular or ventricular arrhythmias, new onset hemorrhagic or ischemic stroke or transient ischemic attack. Outcome measures were: in-hospital and 30-day mortality, length of hospital stay and rate of 30-day re-hospitalisation. RESULTS: A total of 1266 patients were enrolled, of these 23.8% experienced at least a CV event, the majority (15.5%) represented by newly diagnosed decompensated heart failure, and 75% occurring within 3 days. Female gender, a history of CV disease, and more severe pneumonia were predictors of CV events. In-hospital (12.2% vs 4.7%, p < 0.0001) and 30-day (16.3% vs 8.9%, p = 0.0001) mortality was higher in patients with CV events, as well as the re-hospitalisation rate (13.3% vs 9.3%, p = 0.002), and mean hospital stay was 11.4 ± 6.9 vs 9.5 ± 5.6 days (p < 0.0001). The occurrence of CV events during hospitalisation significantly increased the risk of 30-day mortality (HR 1.69, 95% CI 1.14-2.51; p = 0.009). CONCLUSION: Cardiovascular events are frequent in CAP, and their occurrence adversely affects outcome. A strict monitoring might be useful to intercept in-hospital CV complications for those patients with higher risk profile. TRIAL REGISTRATION: NCT03798457 Registered 10 January 2019 - Retrospectively registered.

Lessons learned from COVID-19 for clinical research operations in Italy: what have we learned and what can we apply in the future?

The coronavirus disease 2019 (COVID-19) pandemic has stressed the importance of health research as never before. In the specific domain of clinical research, the effort to rapidly find responses to health challenges and therapeutic hypotheses has highlighted the need for efficient, timely, ethically correct research. The guidelines published by the Agenzia Italiana del Farmaco have shown that some useful changes are feasible: simple and rapid methods have been implemented to conduct clinical research in the emergency conditions of the pandemic, maintaining high levels of quality. In this perspective, four Italian scientific associations operating in clinical research have worked together to evaluate which measures, among the ones implemented during the pandemic, have been particularly significant and potentially effective under normal conditions or in case of emergencies, and that therefore will be useful in the future as well.

Thromboprofilaxys With Fondaparinux vs. Enoxaparin in Hospitalized COVID-19 Patients: A Multicenter Italian Observational Study.

Importance: The use of anticoagulant therapy with heparins decreased mortality in hospitalized patients with severe coronavirus disease 2019 (COVID-19). Even if enoxaparin and fondaparinux have the same clinical indication for venous thromboembolism (VTE) prevention; to date, there are no data about the use of fondaparinux in terms of safety, effectiveness, and impact on clinical prognosis among COVID-19 patients. Objective: To evaluate the safety, effectiveness, and clinical impact of VTE prophylaxis with fondaparinux and enoxaparin among COVID-19 patients hospitalized in internal medicine units. Design, Setting, and Participants: This was a retrospective multicenter observation study, including consecutive symptomatic patients with laboratory-proven COVID-19 admitted to internal medicine units of five Italian hospitals from 15th February to 15th March 2020. Main Outcomes and Measures: The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding; the primary effectiveness outcome was the composite of all events classified as pulmonary embolism and deep venous thrombosis. The secondary effectiveness outcome included acute respiratory distress syndrome and all-cause death. Results: Among 120 COVID-19 patients enrolled in the study, 74 were taking enoxaparin (4,000 or 6,000 units/day) and 46 fondaparinux (2.5 units/day). No statistically significant difference in demographic and laboratory and clinical characteristics between the two groups has been shown. During a median follow-up of 32 (interquartile range: 14-51) days, the cumulative incidence rates of VTE and bleeding events on pharmacological thromboprophylaxis with heparins were 19% and 8%, respectively. The incidence of both VTE (6.5 vs. 13.5%; P = 0.36) and bleeding events (6.5 vs. 4.1%; P = 0.68) did not show a significant difference between COVID-19 patients on fondaparinux compared with those on enoxaparin therapy. The regression model for the risk of outcome events according to different VTE prophylaxis drugs did not show significant differences. Conclusions and Relevance: Although these results need confirmation by prospective studies including a larger population, our study provides preliminary evidence of a safe and efficacy use of fondaparinux for VTE prophylaxis in hospitalized COVID-19 patients.

Fondaparinux Use in Patients With COVID-19: A Preliminary Multicenter Real-World Experience.

The use of heparin has been shown to decrease the mortality in hospitalized patients with severe COVID-19. The aim of our study was to evaluate the clinical impact of venous thromboembolism prophylaxis with fondaparinux versus enoxaparin among 100 hospitalized COVID-19 patients. The incidence of pulmonary embolism, deep venous thrombosis, major bleeding (MB), clinically relevant non-MB, acute respiratory distress syndrome, and in-hospital mortality was compared between patients on fondaparinux versus enoxaparin therapy. The 2 groups were homogeneous for demographic, laboratory, and clinical characteristics. In a median follow-up of 28 (IQR: 12-45) days, no statistically significant difference in venous thromboembolism (14.5% vs. 5.3%; P = 0.20), MB and clinically relevant non-MB (3.2% vs. 5.3%, P = 0.76), ARDS (17.7% vs. 15.8%; P = 0.83), and in-hospital mortality (9.7% vs. 10.5%; P = 0.97) has been shown between the enoxaparin group versus the fondaparinux group. Our preliminary results support the hypothesis of a safe and effective use of fondaparinux among patients with COVID-19 hospitalized in internal medicine units.

Blood Targets of Adjuvant Drugs Against COVID19.

While waiting for the vaccine and/or the best treatment for COVID19, several drugs have been identified as potential adjuvant drugs to counteract the viral action. Several drugs, in fact, have been suggested for their ancillary antiviral role. Viral proteases and peptidases, may interact with well-known drugs such as anticoagulants, antihypertensives, antiserotoninergics and immunomodulants. We here report a basic list of these drugs that include bioflavonoids, heparinoids, ACE inhibitors, angiotensin receptor blockers, antiserotoninergics, and monoclonal antibodies against cytokines that may interact with the viral cycle.

Prevalence and risk factors for pulmonary embolism in patients with suspected acute exacerbation of COPD: a multi-center study.

INTRODUCTION: Pulmonary embolism (PE) prevalence in acute exacerbations of COPD is highly variable. METHODS: To investigate the prevalence and risk factors of PE in patients hospitalized in Departments of Internal Medicine because of AECOPD and suspected PE we conducted a retrospective multicenter study in patients with an AECOPD undergoing chest angio-computed tomography (angio-CT) because of clinical suspect of PE. RESULTS: 1043 patients (mean age 75.8 years ± 9.7 years, 34.5 % women) were included; 132 patients had PE (mean prevalence 12.66%, 95% confidence interval 10.73, 14.77%).) confirmed by angio-CT and 54 patients died during hospitalization (5.18 %). At multivariate analysis, age, female gender, clinical signs and symptoms suggestive of deep vein thrombosis, hypertension, PaCO2 ≤ 40 mmHg, and normal chest-x-ray were significantly associated with a higher PE prevalence. Prevalence of PE in patients with 0, 1, 2, 3 or ≥4 risk factors progressively increase from 1.76 to 30.43%. Mean length of hospitalization (LOH) (15.7 vs 14.2 days, p 0.07) and in-hospital mortality (6.1% vs 5.1%, P=0.62) were slightly but not significantly higher in in patients with PE (6.1% vs 5.1%, P=0.62). CONCLUSIONS: PE prevalence is not negligible in this setting. A number of risk factors may help clinicians in identification of patients at increased risk of PE.

Derivation and Validation of a Prediction Model for Venous Thromboembolism in Primary Care.

BACKGROUND: Most episodes of venous thromboembolism (VTE) occurred in primary care. To date, no score potentially able to identify those patients who may deserve an antithrombotic prophylaxis has been developed. AIM: The objective of this study is to develop and validate a prediction model for VTE in primary care. METHODS: Using the Health Search Database, we identified a cohort of 1,359,880 adult patients between 2002 and 2013. The date of the first General Practitioner's (GP) visit was the cohort entry date. All VTE cases (index date) observed up to December 2014 were identified. The cohort was randomly divided in a development and a validation cohort. According to nested case-cohort analysis, up to five controls were matched to their respective cases on month and year of cohort entry and duration of follow-up.The score was evaluated according to explained variance (pseudo R2) as a performance measure, ratio of predicted to observed cases as model calibration and area under the curve (AUC) as discrimination measure. RESULTS: The score was able to explain 27.9% of the variation for VTE occurrence. The calibration measure revealed a margin of error lower than 10% in 70% of the population. In terms of discrimination, AUC was 0.82 (95% confidence interval: 0.82-0.83). Results of sensitivity analyses substantially confirmed these findings. CONCLUSION: The present score demonstrated a very good accuracy in predicting the risk of VTE in primary care. This score may be therefore implemented in clinical practice so aiding GPs in making decision on patients potentially at risk of VTE.

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use. METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding. RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60). CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).

Acquired Factor XIII Deficiency Inducing Recurrent and Fatal Bleeding, Description of a Case.

Factor XIII deficiency may be inherited or acquired. Inherited deficiency is associated with signs and symptoms of minor bleeding from a young age, and possible major bleeding complications, in particular during pregnancy. On the other hand, acquired factor XIII deficiency is usually associated with severe symptoms of major bleeding, in particular during surgery. In this paper, we report an interesting case of recurrent major bleeding with subsequent fatal bleeding in an adult man diagnosed with acquired factor XIII deficiency.

Correction to: Management of chronic ischemic heart disease into internal medicine and geriatric departments in Italy.

In the original publication of the article.