Editor's Choice - PRINciples of optimal antithrombotiC therapy and coagulation managEment during elective fenestrated and branched EndovaScular aortic repairS (PRINCE2SS): An International Expert Based Delphi Consensus Study.

OBJECTIVE: Management of antithrombotic therapy in patients undergoing elective fenestrated branched endovascular aortic repair (F-BEVAR) is not standardised, nor are there any recommendations from current guidelines. By designing an international expert based Delphi consensus, the study aimed to create recommendations on the pre-, intra-, and post-operative management of antithrombotic therapy in patients scheduled for elective F-BEVAR in high volume centres. METHODS: Eight facilitators created appropriate statements regarding the study topic that were voted on, using a four point Likert scale, by a selected panel of international experts using a three round modified Delphi consensus process. Based on the experts' responses, only those statements reaching Grade A (full agreement ≥ 75%) or B (overall agreement ≥ 80% and full disagreement < 5%) were included in the final document. The round answers' consistency was graded using Cohen's k, the intraclass correlation coefficient, and, in case of double re-submission, the Fleiss k. RESULTS: Sixty-seven experts were included in the final analysis and voted the initial 43 statements related to pre- (n = 15), intra- (n = 10), and post-operative (n = 18) management of antithrombotic drugs. At the end of the process, six statements (13%) were rejected, 20 statements (44%) received a Grade B consensus, and 18 statements (40%) reached a Grade A consensus. Most statements (27; 71%) exhibited very high or high consistency grades, and 11 (29%) a fair or poor grading. The intra-operative statements mostly concentrated on threshold for and monitoring of proper heparinisation. The pre- and post-operative statements mainly focused on indications for dual antiplatelet therapy and its management, considering the possible need for cerebrospinal fluid drainage. CONCLUSION: Based on the elevated strength and high consistency of this international expert based Delphi consensus, most of the statements might guide current clinical management of antithrombotic therapy for elective F-BEVAR. Future studies are needed to clarify the debated issues.

Identifying unanswered questions and setting the agenda for future systematic research in Multiple Sclerosis. A worldwide, multi-stakeholder Priority Setting project.

BACKGROUND: Eliciting the research priorities of people affected by a condition, carers and health care professionals can increase research value and reduce research waste. The Cochrane Multiple Sclerosis and Rare Disease of CNS Group, in collaboration with the Cochrane Neurological Sciences Field, launched a priority setting exercise with the aim of prioritizing pressing questions to ensure that future systematic reviews are as useful as possible to the people who need them, in all countries, regardless of their economic status. METHOD: Sixteen high priority questions on different aspects of MS were developed by members of a multi-stakeholder priority setting Steering Group (SG). In an anonymous online survey translated into 12 languages researchers, clinicians, people with MS (PwMS) and carers were asked to identify and rank, 5 out of 16 questions as high priority and to provide an explanation for their choice. An additional free-text priority research topic suggestion was allowed. RESULTS: The survey was accessible through MS advocacy associations' social media and Cochrane web pages from October 20, 2020 to February 6, 2021. 1.190 responses (86.73% of all web contacts) were evaluable and included in the analysis. Responses came from 55 countries worldwide, 7 of which provided >75% of respondents and 95% of which were high and upper-middle income countries. 58.8% of respondents live in the EU, 23% in the Americas, 8.9% in the Western Pacific, 2.8% in the Eastern Mediterranean and 0.3% in South Eastern Asia. About 75% of the respondents were PwMS. The five research questions to be answered with the highest priority were: Question (Q)1 "Does MRI help predict disability worsening of PwMS?" (19.9%), Q5 "What are the benefits and harms of treating PwMS with one disease-modifying drug compared to another?" (19.3%), Q3 "Does multidisciplinary care by teams of different social and health professionals improve health outcomes and experiences for PwMS?" (11.9%), Q16 "Does psychological health affect disease progression in PwMS?" (9.2%) and Q10 "What are the benefits and harms of exercise for PwMS?" (7.2%). The multivariable logistic regression analysis indicated a significant influence of geographic area and income level on the ranking of Q1 and a marginal for Q16 as top a priority after accounting for the effect of all other predictors. Approximately 50% of the respondents indicated that they had an important additional suggestion to be considered. CONCLUSION: This international collaborative initiative in the field of MS offers a worldwide perspective on the research questions perceived as pivotal by a geographically representative sample of multiple stakeholders in the field of MS. The results of the survey could guide the prioritization of research on pharmacological and non-pharmacological interventions which could be meaningful and useful for PwMS and carers, avoiding the duplication of efforts and research waste. High quality systematic reviews elicited by priority setting exercises may offer the best available evidence and inform decisions by healthcare providers and policy-makers which can be adapted to the different realities around the world.

Influence of clinical presentation, site, and extent of venous thrombosis on decision about duration of anticoagulation: Data from the international, prospective, observational WHITE study.

BACKGROUND: Low attention has generally been dedicated to the influence of clinical presentation, extent of venous thrombosis and presence of residual vein obstruction (RVO) on the decision about the duration of secondary prophylaxis after a first venous thromboembolism (VTE). AIM: This study aimed at investigating the role of the mentioned VTE characteristics on the therapeutic decision using the information collected in the international, prospective, observational WHITE study. RESULTS: 1240 patients were recruited by 79 clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). 35 patients had as index event a pulmonary embolism (PE) without a deep vein thrombosis (DVT), and all continued anticoagulation. We focused on the 1205 subjects with DVT. The treatment decision differed among countries; altogether, more than 85% of patients with proximal (with or without distal) DVT continued a prophylactic treatment with anticoagulants, or antithrombotics; 34% of patients with isolated distal DVT stopped treatment, and more than 85% of patients with a PE associated to a DVT continued treatment. At multivariable analysis, the presence of proximal DVT, signs of post-thrombotic syndrome (PTS), residual vein obstruction (RVO), maintenance <180 days and concomitant diseases was associated with increased probability to continue secondary prophylaxis. CONCLUSION: The presentation as proximal DVT (with or without PE) or isolated PE influenced the treating physicians' decision in favor of extension of secondary prophylaxis, together with the presence of concomitant diseases and local conditions which may increase the risk of post-thrombotic syndrome.

Unprovoked or provoked venous thromboembolism: not the prevalent criterion to decide on anticoagulation extension in clinical practice of various countries-the prospective, international, observational WHITE study.

The decision on treatment after a first venous thromboembolism (VTE) to prevent recurrences may be influenced by many factors. The prospective, observational, WHITE study aimed to analyze how this issue was tackled in every-day clinical practice in various countries, which have sensibly different socio-economic conditions and healthcare systems. Doctors active in 79 Internal or Vascular clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia) enrolled VTE patients after the maintenance treatment phase. The present report analyzed information, collected in the central database, regarding the baseline characteristics, index events, type and duration of anticoagulant therapy and decision on post-maintenance treatment. From April 2018 to December 2020, 1240 patients were enrolled, 58% with an unprovoked index event. Direct oral anticoagulants (DOACs) were used in > 85% of all cases in China, Poland, Portugal, Russia and Czechia, in 52% in Slovakia and in no patient in Tunisia. The maintenance anticoagulation lasted in average approximately 6 months. Altogether, anticoagulation was stopped in 20%, extended in about 50%, regardless of whether the event was unprovoked or provoked and shifted to antithrombotics (mainly sulodexide or aspirin) in the remaining patients. In conclusion, some differences in VTE patient management were found between countries. The provoked/unprovoked nature of the index event, instead, was not the prevalent criterion to drive the decision on extension of anticoagulation, without large variations between countries. DOACs were the most widely used anticoagulant drugs, whereas > 25% of patients received antithrombotic drugs instead of anticoagulants as extended treatment.

Impact of early glomerular filtration rate decline in response to antihypertensive treatment on risk of end-stage kidney disease and cardiovascular outcomes: a systematic review and meta-analysis.

Blood pressure control, which can induce a slight decrease in the glomerular filtration rate (GFR), plays a nephron- and cardioprotective role. However, the more important early decline in GFR associated with antihypertensive therapy and strict blood pressure targets is still of concern. Since few data are available from trials and observational studies, and the phenomenon is relatively rare, we performed a meta-analysis of available studies. We conclude that major reductions in the glomerular filtration rate occurring soon after starting angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and/or under intensive blood pressure control predict end-stage kidney disease.

Anticoagulation Duration After First Venous Thromboembolism: Real-Life Data From the International, Observational WHITE Study.

BACKGROUND: International guidelines recommend at least three months anticoagulation in all patients after acute venous thromboembolism (VTE) and suggest those with unprovoked events be considered for indefinite anticoagulation if the risk of recurrence is high and the risk of bleeding during treatment non-high. Other authors have recently argued against using a dichotomy unprovoked/provoked events to decide on anticoagulation duration and suggest instead using overall risk factors present in each patient as the basis for deciding. AIM: This sub-analysis of the WHITE study aimed at assessing the reasons for the treatment decisions taken by doctors in different countries. RESULTS: 1240 patients were recruited in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). Anticoagulation was extended in 51.7% and 49.3% of patients with unprovoked or provoked events (n.s.); stopped in 15.4% versus 28.9% (P < .0001), and changed to antithrombotic drugs (sulodexide or aspirin) in 32.9% versus 21.8% (P < .0001). In the 430 subjects with isolated distal deep vein thrombosis (IDDVT) anticoagulation was stopped in 34.4%, continued in 37.0% (mainly those with post-thrombotic syndrome [PTS]) and switched to antithrombotics in the balance. High risk of recurrence was the most prevalent reason (>83% of cases) given to continue anticoagulation, regardless of nature and site of the index events, followed by risk of bleeding and presence of PTS signs. CONCLUSION: On average, attending physicians estimated the risk of recurrence in real life conditions, and the consequent therapeutic decision, using all the information available, not limiting to the location or nature of the index event.

People with amyotrophic lateral sclerosis and their caregivers: what matters most?

OBJECTIVES: The aim of this study is to collect the perspectives and values of people affected by amyotrophic lateral sclerosis (ALS) and their carers to offer clinicians, researchers and policymakers aspects which are precious in prioritising future research questions and reshaping care service organisations in a participatory approach. DESIGN AND SETTING: Cohort study using ALS Umbria, the electronic database in Italy. PARTICIPANTS: Eleven patients and 33 carers who agreed to participate in the study were divided into six focus groups by 'status' (patient or carer) and by four severity levels of 'burden of disease'. METHODS: A semiquantitative analysis was undertaken. Each recorded group discussion was transcribed into text file and independently read by two psychologists and two ALS specialists to blindly identify needs, emotions and medical issues, which are the key semantic meanings expressed. Any disagreement in interpretation was resolved through consultation among authors. RESULTS: Carers pronounced significantly more words related to patient's disease burden they cared. 40% of subjects expressed the need for 'assistance', regardless of the disease burden. 'Anger' alone represented more than 1/4 of all expressed emotions and was more common in patients than in carers (73% vs 36%, p=0.077). The most frequent medical issue expressed by 1/3 of participants was 'difficulty in communication'. CONCLUSION: This study has given voice to the expectations of those affected by the burden of ALS. 'Welfare assistance', 'anger management' and resolution of 'difficulties in communication' represent issues that need to be analysed in a common prioritised research agenda with sensible and shared outcome measures to implement patient-centred medicine.

Sulodexide for Diabetic-Induced Disabilities: A Systematic Review and Meta-Analysis.

INTRODUCTION: Micro- and macrovascular complications of diabetes are leading morbidities in the world population. They are responsible not only for increased mortality but also severe disabilities, which jeopardize quality of life (e.g., blindness, walking limitations, and renal failure requiring dialysis). The new antidiabetic agents (e.g., glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter inhibitors) are increasingly recognized as breakthrough agents in the treatment of diabetes and prevention of diabetic complications. However, drugs effective in preventing and treating diabetic disabilities are still needed and sulodexide could be one of those able to address the unmet clinical needs of the new antidiabetic agents. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal. We also manually searched potentially relevant journals, conference proceedings, and journal supplements. Any study monitoring any effect of sulodexide in subjects with diabetes, in relation to renal, vascular, and ocular complication, was considered. Treatment effects were estimated using standardized mean differences (SMDs), mean differences (MDs), and risk ratios (RRs), as appropriate. We calculated 95% confidence interval (CIs) and heterogeneity (Q, tau, and I2). RESULTS: The search found 45 studies with 2817 participants (mean age 57 years; 63% male). The 26 randomized controlled studies included 2074 participants (mean age 58.8 years; 66% male). Sulodexide reduced the impact of diabetic retinopathy; increased the pain-free and maximal walking distance in peripheral arterial disease; accelerated the healing of diabetes-associated trophic ulcers; and decreased the rate of albumin excretion in subjects with nephropathy. The risk of adverse events (AEs) was not different between sulodexide and controls. CONCLUSION: Sulodexide has a beneficial effect on the ocular, peripheral arterial disease, trophic ulcers, and renal complications of diabetes without increasing the risk of AEs.

Design and rationale of a randomized, placebo-controlled trial on the efficacy and safety of sulodexide for extended treatment in elderly patients after a first venous thromboembolism.

How to prevent recurrences after a first venous thromboembolic (VTE) event in elderly patients is still an open issue, especially because of the high bleeding risk of anticoagulation in these patients. The placebo-controlled "Jason" study aims at assessing the efficacy and safety for secondary VTE prevention in elderly patients of oral Sulodexide (Vessel®) administration, a mixture of glycosaminoglycans (Alfasigma, Bologna, Italy) which proved effective against recurrences in a general population (SURVET study) without major bleeding (MB) complications. 1450 patients, aged ≥ 75 years, after at least 3 months of anticoagulation treatment for a first VTE episode, are double-blind randomized to receive for 12 months either sulodexide 500 lipasemic units (LSUs) twice daily, or sulodexide 250 LSU twice daily + indistinguishable placebo, or indistinguishable placebo. Primary outcomes for efficacy are the composite of death for VTE and recurrent VTE, and occurrence of MB for safety. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, and MB + clinically relevant non-MB. The first patient is scheduled to be randomized in May 2020. The study protocol has been approved by AIFA (Agenzia Italiana del Farmaco) and the Ethics Committee of the coordinating center. Written informed consent will be obtained from all patients prior to study participation. Jason study is an investigator-initiated trial, promoted by "Arianna Anticoagulazione" Foundation, Bologna, Italy, and supported by Alfasigma, Bologna, Italy. Study findings will be disseminated to participant centers, at research conferences and in peer-reviewed journals. Trial registration numbers NCT04257487; EudraCT (2019-000570-33).

Is there inter-observer variation in the interpretation of SSEPs in comatose cardiac arrest survivors? Further considerations following the Italian multicenter ProNeCa study.

BACKGROUND: Bilateral absence of N20 peak in median nerve Somatosensory Evoked Potentials (SSEPs) is considered the most valid predictor of poor outcome in comatose survivors after cardiopulmonary resuscitation. We investigated the consistency in interpreting SSEP recordings in a multicentre study. METHODS: 44 SSEP recordings randomly extracted from 600 recordings of 392 patients included in the "Prognostication of Neurological outcome after Cardiac Arrest (ProNeCa) study" were blindly read by three expert neurophysiologists. Agreement between raters, and individual agreement of each rater vs. reference standard (RS), were calculated using Kappa Coefficients. Inter-rater reliability was calculated with Intra-class Correlation Coefficient (ICC). RESULTS: When raters had to evaluate the presence of N20 with normal amplitude, the inter-rater agreement was very high (Kappa = 0.84). In the case of N20 absence the agreement was good (Kappa = 0.66), but when N20 amplitude was low, the agreement decreased to moderate (Kappa = 0.579) becoming even weaker when it was "Non Assessable" (Kappa = 0.107). The agreement of each rater with the RS had a range from moderate to very good; rater1 Kappa = 0.589 (95%CI 0.397-0.781; p < 0.001), rater2 Kappa = 0.644 (95%CI 0.460-0.828; p < 0.001), rater3 Kappa = 0.859 (95%CI 0.698-1.000; p < 0.001). The ICC was barely good, 0.682 (95%CI 0.539-0.798; p = 0.0075). CONCLUSION: Different health professionals, using different equipment in a multicentre study, had very good inter-rater agreement in interpreting SSEP records. The interpretation of "Non Assessable" SEPPs, mainly in relation to noise level, is still a crucial issue because it increases rater uncertainty. For this reason, it is important to focus on improving recording quality and interpretation of records.

Sulodexide for the Symptoms and Signs of Chronic Venous Disease: A Systematic Review and Meta-analysis.

INTRODUCTION: Chronic venous disease (CVD) is a common condition associated with valvular dysfunction, venous hypertension and endothelial inflammation. Sulodexide facilitates the healing of venous ulcers and is frequently used in patients with CVD without ulcer. This review assessed the efficacy and safety of sulodexide for treatment of signs and symptoms of lower extremity CVD. METHODS: We searched MEDLINE, EMBASE, CINAHL and AMED as well as the Cochrane Central Register of Controlled Trials and the World Health Organisation (WHO) International Clinical Trials Registry Platform Search Portal. We also manually searched potentially relevant journals, conference proceedings and journal supplements. Any study monitoring any effect of sulodexide in patients with CVD at any stage of the disease, classified or non-classified, was considered. Treatment effects were estimated using standardised mean differences (SMDs), mean differences (MDs) and risk ratios (RRs), as appropriate. We calculated 95% confidence intervals (CIs) and heterogeneity (Q, tau and I2). RESULTS: The search found 64 studies, but only 23 provided data on 7153 participants (mean age 55 years; 68% female). The 13 studies providing extractable quantitative information included 1901 participants (mean age 55.2 years; 65% female). Sulodexide decreased the intensity of pain, cramps, heaviness, oedema and total symptom score and reduced inflammatory mediators in patients with CVD. The risk of adverse events (AEs) was not different between sulodexide and placebo or heparan sulphate (RR 1.31, 95% CI 0.74-2.32; I2 = 0%; 270 participants). The overall risk of AEs with sulodexide was low: 3% (95% CI 1-4%) estimated from 3656 participants. CONCLUSION: Sulodexide was found to have a beneficial venoactive effect on the major signs and symptoms of CVD such as pain, cramps, heaviness and oedema without increasing the risk of AEs. It is also likely to exert a systemic effect on the course of CVD by interfering with inflammatory chemokines.

Is it worth it, or possible, to measure what matters to patients with epilepsy and their caregivers?

OBJECTIVE: The objective of this study was to collect perspectives, ideas, and values of people affected by epilepsy and their carer to include them in new research in this area. DESIGN: This is a semiquantitative study analyzing needs, emotions, and medical issues emerging from focus groups with patients and carers divided in three severity levels of disease. PARTICIPANTS: The participants were 25 patients and 36 carers attending outpatients' service of tertiary epilepsy center in Umbria, Italy. RESULTS: Assistance was the need expressed by more than 40% of the participants followed by experience-sharing, knowledge, control, clarity, and security. The only significant effect in logistic regression analysis after adjusting for severity was the patients' expressed need for "experience-sharing" more than their carers (OR 7.29, 95%CI: 1.76-30.18). Hope was the emotion expressed by more than 50% of the participants, followed by anger, fear, and resignation. After adjusting for severity, carers were more likely to express anger, in comparison with patients (OR 17.23, 95%CI: 3.55-83.74; P<0.001). The patients were 6.88 times more likely (95%CI 1.84-25.75; P=0.004) to express "resignation" than their carers. The most frequent medical issues were related to: "medications", "frequency of crises", "work impact", "quality of life", "psychomedical integration of care", and "development of new drugs". After adjusting for severity in a logistic regression analysis, patients were more likely to express concerns for the frequency of crises than carers (OR 3.57, 95%CI: 1.16-11.04; P=0.027). CONCLUSIONS: Patients' and carers' priorities, based on intense personal insight, represent a starting point to work for shared outcome measures in clinical trials and shared agenda in research, including research of strong evidence in complex intervention as service models for people with epilepsy.

Integrated Imaginative Distention Therapy to Cope with Fatigue. DIMMI SI Study: The First Randomized Controlled Trial in Multiple Sclerosis.

INTRODUCTION: Fatigue is a frequent, disabling, and difficult to treat symptom in neurological disease and in other stress-related conditions; Integrated Imaginative Distention (IID) is a therapy combining muscular and imaginative relaxation, feasible also in disabled subjects; the DIMMI SI trial was planned to evaluate IID efficacy on fatigue. METHODS: The design was a parallel, randomised 1:1 (intervention:waiting list), controlled, open-label trial. Participants were persons with multiple sclerosis (pwMS), persons with insomnia (pwINS), and health professionals (HP) as conditions related to fatigue and stress. The primary outcome was the post-intervention change of fatigue; secondary outcomes were changes in insomnia, stress, and quality of life (QoL). Eight IID weekly training group sessions were delivered by a skilled psychotherapist. The study lasted 12 months. RESULTS: One hundred and forty-four subjects were enrolled, 48 for each condition. The mean change in Modified Fatigue Impact Scale (MFIS) score among exposed was 7.7 [95% CI 1.1, 14.4] (P = 0.023) in pwMS; 7.1 [1.9, 12.3] (P = 0.007) among pwINS, and 11.3 [4.3, 18.2] among HP (P = 0.002). At the last follow-up, the benefit was confirmed on physical fatigue for pwMS, on total fatigue for pwINS and HP. CONCLUSIONS: DIMMI SI is the first randomized controlled trial evaluating the efficacy of IID on fatigue. IID resulted a complementary intervention to reduce fatigue in stress-related conditions, in both health and disease status. NCT02290990ClinicalTrials.gov.

Correction: Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

[This corrects the article DOI: 10.1371/journal.ppat.1006299.].

Novel decay dynamics revealed for virus-mediated drug activation in cytomegalovirus infection.

Human cytomegalovirus (CMV) infection is a substantial cause of morbidity and mortality in immunocompromised hosts and globally is one of the most important congenital infections. The nucleoside analogue ganciclovir (GCV), which requires initial phosphorylation by the viral UL97 kinase, is the mainstay for treatment. To date, CMV decay kinetics during GCV therapy have not been extensively investigated and its clinical implications not fully appreciated. We measured CMV DNA levels in the blood of 92 solid organ transplant recipients with CMV disease over the initial 21 days of ganciclovir therapy and identified four distinct decay patterns, including a new pattern exhibiting a transient viral rebound (Hump) following initial decline. Since current viral dynamics models were unable to account for this Hump profile, we developed a novel multi-level model, which includes the intracellular role of UL97 in the continued activation of ganciclovir, that successfully described all the decline patterns observed. Fitting the data allowed us to estimate ganciclovir effectiveness in vivo (mean 92%), infected cell half-life (mean 0.7 days), and other viral dynamics parameters that determine which of the four kinetic patterns will ensue. An important clinical implication of our results is that the virological efficacy of GCV operates over a broad dose range. The model also raises the possibility that GCV can drive replication to a new lower steady state but ultimately cannot fully eradicate it. This model is likely to be generalizable to other anti-CMV nucleoside analogs that require activation by viral enzymes such as UL97 or its homologues.

Lessons Learned From a Randomized Study of Oral Valganciclovir Versus Parenteral Ganciclovir Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients: The VICTOR Trial.

The VICTOR study showed comparable efficacy of treatment with intravenous ganciclovir and oral valganciclovir for cytomegalovirus (CMV) disease in solid organ transplant recipients. Oral therapy is now recommended treatment in clinical practice and guidelines. The VICTOR biobank was used in a series of post hoc analyses that yielded unique and clinically valuable insights into CMV treatment and pathogenesis. For example, the importance of tailoring therapy to initial viral load, the effect of immunosuppression on outcomes, and the need to continue therapy until undetectable viral load to prevent recurrence and emergence of resistant strains. Data were also used to validate the use of international units (IU) in quantitative measurements of CMV DNAemia, which may help future studies to define relevant cutoffs for treatment guidance. The analyses also showed the importance of inflammation on viral outcomes and identified potential targets for future studies. Here we summarize the valuable lessons learned from analysis of the VICTOR data set and sample repository.

Sulodexide for the Prevention of Recurrent Venous Thromboembolism: The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Patients with a first episode of unprovoked venous thromboembolism have a high risk of recurrence after discontinuation of anticoagulant therapy. Extending anticoagulation reduces the risk of recurrence but is associated with increased bleeding. Sulodexide, a glycosaminoglycan, exerts antithrombotic and profibrinolytic actions with a low bleeding risk when administered orally, but its benefit for preventing recurrent venous thromboembolism is not well known. METHODS AND RESULTS: In this multicenter, double-blind study, 615 patients with first-ever unprovoked venous thromboembolism who had completed 3 to 12 months of oral anticoagulant treatment were randomly assigned to sulodexide 500 lipasemic units twice daily or placebo for 2 years, in addition to elastic stockings. The primary efficacy outcome was recurrence of venous thromboembolism. Major or clinically relevant bleeding was the primary safety outcome. Venous thromboembolism recurred in 15 of the 307 patients who received sulodexide and in 30 of the 308 patients who received placebo (hazard ratio, 0.49; 95% confidence interval [CI], 0.27-0.92; P=0.02). The analysis in which lost to follow-up was assigned to failure yielded a risk ratio among treated versus control subjects of 0.54 (95% confidence interval, 0.35-0.85; P=0.009). No major bleeding episodes occurred; 2 patients in each treatment group had a clinically relevant bleeding episode. Adverse events were similar in the 2 groups. CONCLUSION: Sulodexide given after discontinuation of anticoagulant treatment reduced the risk of recurrence in patients with unprovoked venous thromboembolism, with no apparent increase of bleeding risk. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu/. Identifier: EudraCT number 2009-016923-77.

Increased osteoprotegerin predicts poor virological outcome during anticytomegalovirus therapy in solid organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection involves interaction between endothelial cells and leukocyte subsets that may promote vascular inflammation and lead to treatment failure in infected individuals. Osteoprotegerin is a marker of vascular and systemic inflammation but has not been investigated in relation to treatment outcome during CMV infection. METHODS: We investigated whether circulating levels of osteoprotegerin are related to features of CMV disease and treatment outcomes during CMV infection in 291 solid organ transplant recipients receiving valganciclovir or ganciclovir in an international multicenter trial of CMV disease treatment (the VICTOR study). RESULTS: Elevated plasma osteoprotegerin was associated with (i) certain disease characteristics including presence of tissue invasive disease (P<0.05) and increased viral load at baseline (P<0.05), (ii) poor virological outcome at day 49 after anti-CMV therapy, (iii) increased plasma levels of markers of inflammation (pentraxin 3 and C-reactive protein) and endothelial cell activation (von Willebrand factor) both at baseline and during follow-up. CONCLUSION: Our finding indicates that elevated osteoprotegerin levels in solid organ transplant recipients with CMV infection may reflect vascular inflammation and is associated with late virological outcome in these patients.