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.

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.

Role of Internal Jugular Vein Ultrasound Measurements in the Assessment of Central Venous Pressure in Spontaneously Breathing Patients: A Systematic Review.

BACKGROUND: Few studies have tested the role of the internal jugular vein (IJV) ultrasonographic (US) diameters in the assessment of central venous pressure (CVP) in spontaneously breathing patients. No review or meta-analysis is currently available on the role of IJV assessment in this setting. The aim of this systematic review is to check the reliability and accuracy of IJV US diameters in predicting CVP and to evaluate its correlation with CVP in spontaneously breathing patients. METHODS: This systematic review was based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We included studies on the accuracy and reliability of the IJV ultrasound measures and studies exploring its correlation with CVP in adult spontaneously breathing patients. The studies' report quality was assessed by Standards for Reporting of Diagnostic Accuracy (STARD) and Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 scales. RESULTS: A total of five studies was eligible for final analysis. The studies on IJV ultrasound measures showed a good quality in reporting. The anterior-posterior diameter maximum of IJV (AP-IJV Dmax) showed the best correlation with the CVP with a good inter-rater reliability and validity in predicting CVP. All measures showed good inter-rater reliability and validity in predicting CVP, but only the AP-IJV Dmax showed good correlation with CVP. CONCLUSIONS: The AP-IJV Dmax could be a potential surrogate of CVP because of its good reliability and validity in predicting CVP value and its fair-moderate correlation with CVP. Anyway, further research should confi rm these conclusions.

Effect of the immunosuppressive regimen on the incidence of cytomegalovirus infection in 378 heart transplant recipients: A single centre, prospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection is a major complication of immunosuppression after heart transplant. Recent studies suggest the actual immunosuppressive regimen may affect the risk of CMV infection. OBJECTIVES: To evaluate incidence, risk factors and clinical consequences of CMV infection and assess the possible differential effect of distinct immunosuppressive protocols. STUDY DESIGN: Single centre, prospective cohort study of 378 consecutive heart transplant recipients undergoing CMV monitoring. Preemptive treatment was the standard of care. Patients were grouped as follows: group A, without any CMV infection; group B, with CMV infection not requiring pre-emptive treatment; group C, treated for CMV infection or disease. RESULTS: Most recipients never required antiviral therapy because of no CMV infection/disease (group A, 31%) or CMV levels below the cut-off for pre-emptive treatment (group B, 28%). Group C recipients (41%) were significantly older than group A patients (49.1±13.2 vs. 44.8±15.1 years; p=0.028). Most cases occurred within the second month post-transplant. CMV viremia was detected in 77% and 62% of patients primed with thymoglobulin or ATG Fresenius, respectively, (OR 2.06, 95% C.I. 1.27-3.34; p=0.0034). Use of everolimus was associated with a significantly lower rate of CMV infection compared to azathioprine or mycophenolate (OR 0.19, 95% C.I. 0.09-0.39; p<0.0001). Major opportunistic infections were significantly more common in groups B and C. CONCLUSION: In a large and homogeneous cohort of heart transplant recipients, we observed a strong relationship between the immune suppressive regimen and CMV infection, as well as an increased incidence of other opportunistic infections in recipients with CMV infection/disease.

Recipient-born bloodstream infection due to extensively drug-resistant Acinetobacter baumannii after emergency heart transplant: report of a case and review of the literature.

Infections due to drug-resistant Gram-negative rods are an emerging risk factor for increased mortality after solid organ transplant. Extensively drug-resistant (XDR) Acinetobacter baumannii (Acb) is a major threat in several critical care settings. The limited available data on the outcome of XDR Acb infections in organ transplant recipients mostly comes from cases of donor-derived infections. However, recipients of life-saving organs are often critically ill patients, staying long term in intensive care units, and therefore at high risk for nosocomial infections. In this report, we describe our experience with the exceedingly complex management of a recipient-born XDR Acb bloodstream infection clinically ensued shortly after heart transplant. We also review the current literature on this mounting issue relevant for intensive care, transplant medicine and infectious diseases.

Infective endocarditis due to multidrug resistant gram-negative bacilli: single centre experience over 5 years.

BACKGROUND: Infective endocarditis (IE) due to gram-negative (GN) bacilli is uncommon. Although multi- and extensively-drug resistant (MDR/XDR) GN infections are emerging, very few data are available on IE due to these microrganisms. METHODS: In this study, we describe the clinical characteristics, course and outcome of five contemporary, definite, MDR/XDR GNIE cases seen at our centre. RESULTS: All patients had been admitted to a hospital during the 6months before IE onset, 2 were on hemodialysis and 3 on intravenous medications. Three of the 5 cases were hospital-acquired. Intracardiac prosthetic devices were present in all cases (3 central venous lines, 2 prosthetic heart valves, 2 pacemakers). Mean Charlson comorbidity index was 5.8. Causative pathogens were XDR Pseudomonas aeruginosa (2 cases), XDR Acinetobacter baumannii, MDR Burkolderia cepacia and MDR Escherichia coli (1 case each). Concomitant pathogens with a MDR/XDR phenotype were isolated in 4 patients. Both valves and intracardiac devices and left and right sides of the heart were involved. The rate of complications was high. Antibiotic treatment hinged on the use of colistin, a carbapenem or both. Cardiovascular surgical procedures were performed in 3 patients. Despite aggressive therapeutic regimens, outcomes were poor. Clearance of bacteremia was obtained in 3 patients, in-hospital death occurred in 3 patients, only 1 patient survived during follow up. CONCLUSIONS: MDR/XDR GN are emerging as a cause of IE in carriers of intracardiac prostheses with extensive healthcare contacts and multiple comorbidities. Resistant GNIE has a complicated course and shows a dismal prognosis.

Pattern of resolution of pulmonary hypertension, long-term allograft right ventricular function, and exercise capacity in high-risk heart transplant recipients listed under oral sildenafil.

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three-yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high-risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One- and three-yr RHCs confirmed stable PH reversal (n = 26, all three-yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo2 peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco2 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long-term survival in PH recipients initially disqualified.

Adefovir treatment for chronic hepatitis B in heart transplant recipients.

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice-monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV-DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild-to-moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV-DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV-DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine-resistant chronic hepatitis B.

Current trends in the management of cardiac implantable electronic device (CIED) infections.

Cardiac implantable electronic device (CIED) infections are an emerging clinical problem. A growing number of dedicated and high quality clinical studies are currently being generated. We here review the most recent advances in the diagnosis and treatment of patients with CIED infection including intracardiac lead endocarditis. We discuss the current etiology and risk factors, and appraise the major diagnostic issues, describing our center's therapeutic approach. We also address the management of CIED infection complications.

High-dose daptomycin for cardiac implantable electronic device-related infective endocarditis.

BACKGROUND: Cardiac implantable electronic device (CIED)-related endocarditis is a growing challenge because of increasing incidence and significant mortality. Current treatment is based on complete hardware removal coupled with long-term administration of effective and safe antimicrobials. Daptomycin at the dose of 6 mg/kg/day has been found to be effective in staphylococcal endocarditis, but limited data exist on CIED endocarditis. Moreover, whether higher doses could be more effective but equally safe in this setting is currently unknown. METHODS: We report here our experience with high-dose daptomycin in the treatment of 25 cases of CIED endocarditis due to staphylococci. RESULTS: Patients were mostly elderly and male, with large lead vegetations and severe comorbidities. Pathogens were Staphylococcus epidermidis (56%), Staphylococcus aureus (28%), and other coagulase-negative staphylococci (16%). Only 4 patients (16%) had a normal pretreatment renal function. The median daptomycin daily dose was 8.3 mg/kg (range, 6.4-10.7). Daptomycin was administered for a median of 20 days (range, 8-52). Percutaneous lead extraction was performed in 88% of patients. Two patients (8%) failed to clear bacteremia. The overall clinical success of treatment was 80%, whereas a complete microbiological success was observed in 92% of patients. Creatine phosphokinase values were monitored and increased above normal in 5 cases (20%). No serious adverse event related to high-dose daptomycin was observed and no patient required discontinuation because of muscle toxicity. CONCLUSIONS: Our experience suggests that high-dose daptomycin may be a safe therapeutic option in staphylococcal CIED endocarditis and may be associated with high microbiological responses and clinical success.

Carcinoid Heart Disease: A Rare Cause of Right Ventricular Dysfunction Evaluation by Transthoracic 2D, Doppler and 3-D Echocardiography.

Carcinoid heart disease is a rare cause of heart failure with or without right valvular heart impairments. In this study, we showed a case of carcinoid tumour with hepatic metastases inducing carcinoid heart disease. Neuroendocrine heart involvement happens for severe tricuspid valve insufficiency and plaques on right ventricular (RV) walls produced by a release of serotonin (5-HT). A patient affected by primitive ileal tumour with 5-HT-secernent hepatic metastases inducing tricuspid insufficiency is showed. Transthoracic 2-D echocardiography showed tricuspid valve regurgitation and both right atrium, RV-walls plaques and RV dilation. Continue-wave Doppler showed a characteristic "dagger shaped" spectrum of tricuspid systolic flow. RV function was evaluated with 3-D transthoracic echocardiography. In particular, RV volumes, RV ejection fraction and stroke volume were defined by this technique. 2, 3-D echocardiography and Doppler method are useful techniques to show heart valves' derangements and RV function to non-invasively detect RV impairments in carcinoid heart disease.