Angelo Bignamini

Carotid Artery Stenting First Consensus Document of the ICCS-SPREAD Joint Committee

Background and Purpose— The prevention of stroke and the correct treatment of carotid artery stenosis represent today a major debate in cardiovascular medicine. Beside carotid endarterectomy, carotid angioplasty and stenting is becoming more widely performed for the treatment of severe carotid obstructive disease, and is now accepted as a less invasive technique that may provide an alternative for selected patients, particularly those with significant comorbidities. An Italian multidisciplinary task force, in which converged the most representative scientific societies involved in carotid treatment, was created to provide neurologists, radiologist, cardiologists, vascular surgeons, and all those involved in prevention and treatment of carotid disease with a simple, clear and updated evidence-based consensus document. Summary of Review— This First Consensus Document of the ICCS (Italian Consensus Carotid Stenting)/SPREAD group addressed the main issues related to methodology, definition of symptomatic and asymptomatic carotid stenosis, indication and procedures for carotid artery stenting, including the use of devices for preventing procedural embolic complications. Special attention was paid to credentials and competency for physicians qualifications to perform vascular angioplasty and stent placement, including training, acceptable complication rates and certification. Conclusions— As any guideline or consensus statement, also this document is valid as long as the evidence on which it is based remains up-to-date. In such a fast-evolving field of medicine as the management of carotid stenosis, it is mandatory to stimulate a continuous and fruitful discussion among all the professionals involved in this very evolutionary field.

Long-Term Outcomes of CMV Disease Treatment with Valganciclovir Versus IV Ganciclovir in Solid Organ Transplant Recipients

Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long‐term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3–11.3], p = 0.012; virological: OR 5.6 [2.5–12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long‐term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.

Secondary Prevention of Stroke in Italy: A Cross-Sectional Survey in Family Practice

Background— Hypertension control and antiplatelet or oral anticoagulant drugs are the basis for secondary prevention of cerebrovascular events. Family physicians (FPs) are usually involved in both aspects of prevention, but no research has been carried out in Italy to evaluate the behavior of FPs in this field of prevention. Methods— Data concerning 318 Italian FPs and 465 061 patients were extracted from the Health Search Database. Patients with coded diagnoses of stroke and transient ischemic attack (TIA) were selected. Demographic records and information regarding presence of concurrent disease and medical records were also obtained. Logistic regression analyses were carried out to assess whether conditions exist that make appropriate control of blood pressure (BP) and prescription of antiplatelet or anticoagulant drugs more likely. Results— We selected 2555 patients with diagnosis of stroke and 2755 with TIA. Among all of the subjects, 32.6% had no BP recorded. Among the remaining subjects, 58.7% reported uncontrolled BP. Isolated systolic hypertension has been shown in 68.8% of patients with uncontrolled BP. Antiplatelet and anticoagulant drugs were prescribed in 72% of these cases. Factors that made the prescription significantly more unlikely were diagnosis of TIA (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.41 to 0.54), total invalidity (OR, 0.66; 95% CI 0.56 to 0.78), and time from event of 5 years or more (OR, 0.81; 95% CI, 0.70 to 0.94). Conclusions— Italian FPs could improve secondary prevention of cerebrovascular accidents. The primary target of intervention should be the control of systolic BP, and the group of patients with unacceptably high BP should be given priority. All of these patients should have been prescribed antiplatelet drugs or anticoagulant agents, except in cases of extremely short life expectancy or substantial contraindications.

Impact of Genetic Polymorphisms in Cytomegalovirus Glycoprotein B on Outcomes in Solid-Organ Transplant Recipients with Cytomegalovirus Disease

BACKGROUND It is unknown whether specific viral polymorphisms affect in vivo therapeutic response in patients with cytomegalovirus (CMV) disease. Polymorphisms in the CMV glycoprotein B (gB) gene allow discrimination of 4 distinct genotypes (gB1-gB4). We assessed the influence of gB genotypes on the clinical and virologic outcome of CMV disease. METHODS Solid-organ transplant recipients enrolled in a multicenter trial of CMV disease treatment (VICTOR study) were included in this study. CMV gB genotyping was performed using quantitative real-time polymerase chain reaction at day 0 (start of antiviral therapy). RESULTS Among 239 patients with CMV disease, the prevalence of gB strain types was 26% for gB1, 10% for gB2, 10% for gB3, and 5% for gB4, whereas mixed infections were present in 49%. Donor-seropositive/recipient-seropositive patients were more likely to have mixed gB infection than donor-seropositive/recipient-seronegative patients (40% vs. 12%; P = .001). Median baseline viral loads were higher and time to viral eradication was longer ( P = .006 and P = .026 , respectively) for mixed infection versus infection with a single genotype. In a multivariate model, mixed gB infection was a significant predictor of failure to eradicate virus by day 21 (mixed vs single genotype; odds ratio, 2.66; 95% confidence interval, 1.31-5.38; P = .007 ) after controlling for baseline viral load, CMV serostatus at baseline, ganciclovir resistance, and antiviral treatment. No effect of gB genotype was seen on virologic or clinical CMV recurrence. CONCLUSIONS No specific gB genotype appears to confer a specific CMV virulence advantage. However, mixed gB genotype infections are associated with higher viral loads and delayed viral clearance.

Helmet Continuous Positive Airway Pressure vs Oxygen Therapy To Improve Oxygenation in Community-Acquired Pneumonia A Randomized, Controlled Trial

OBJECTIVE Our objective was to evaluate the efficacy of noninvasive continuous positive airway pressure (CPAP) delivered by helmet in improving oxygenation in comparison with oxygen therapy in community-acquired pneumonia (CAP). METHODS This was a multicenter, randomized, controlled trial enrolling patients with CAP admitted to an ED with moderate hypoxemic acute respiratory failure (ARF) (Pa(O(2))/Fi(O(2)) ratio > or = 210 and < or = 285). Patients were randomized to helmet CPAP or standard oxygen therapy (control group). The primary end point was the time to reach a Pa(O(2))/Fi(O(2)) ratio > 315. After reaching this value, patients randomized to CPAP were switched to oxygen, and the proportion of subjects who could maintain a Pa(O(2))/Fi(O(2)) ratio > 315 at 1 h was recorded. RESULTS Forty-seven patients were recruited: 20 randomized to CPAP and 27 to controls. Patients randomized to CPAP reached the end point in a median of 1.5 h, whereas controls reached the end point in 48 h (P < .001). The proportion of patients who reached the primary end point was 95% (19/20) among the CPAP group and 30% (8/27) among controls (P < .001). One hour after reaching the primary end point, 2/14 patients in the CPAP group maintained a Pa(O(2))/Fi(O(2)) value > 315. CONCLUSIONS CPAP delivered by helmet rapidly improves oxygenation in patients with CAP suffering from a moderate hypoxemic ARF. This trial represents a proof-of-concept evaluation of the potential usefulness of CPAP in patients with CAP.

Effects of the Intensity of Immunosuppressive Therapy on Outcome of Treatment for CMV Disease in Organ Transplant Recipients

An effective host immune response, critical for successful control of Cytomegalovirus (CMV) disease in solid organ transplant recipients, is affected by intensity and type of immunosuppressive therapy. We used information prospectively captured in the VICTOR‐trial to investigate the impact of immunosuppressive therapy on short‐ and long‐term outcomes of CMV treatment in organ transplant recipients. Dual, as compared to triple, immunosuppressive therapy ([odds ratios] OR of 2.55; 95% CI: 1.51–4.60; p = 0.002), lower blood concentrations of calcineurin inhibitors (OR of 5.53; CI: 1.04–29.35; p = 0.045), and longer time since transplantation (OR of 1.70; CI: 1.01–2.87; p = 0.047) all showed better early (Day 21) CMV DNAemia eradication. We observed no effect of the intensity of the immunosuppressive therapy on overall rates of viral eradication or recurrence. The type of calcineurin inhibitor (tacrolimus/cyclosporine) or use of mycophenolate did not affect treatment efficacy, although both tacrolimus and mycophenolate treated patients showed a lower rate of virological recurrence OR 0.51 (95% CI: 0.26–0.98; p = 0.044) and OR 0.45 (95% CI: 0.22–0.93; p = 0.031), respectively. Lower total intensity of immunosuppressive therapy was associated with more effective early, but not overall, CMV DNAemia eradication by valganciclovir/ganciclovir therapy. Both mycophenolate and tacrolimus (rather than cyclosporine) therapy seem to be associated with reduced risk of recurrence.

Carotid plaque morphology improves stroke risk prediction: usefulness of a new ultrasonographic score.

Carotid thickening and plaque detected by B-mode imaging ultrasound are useful to improve the ischemic risk evaluation in asymptomatic subjects over and beyond the traditional cardiovascular risk factors. Some plaque’s echographic parameters help describing the vascular risk. We hypothesized that the stenosis degree, plaque surface irregularity, echolucency and texture, compounded in a Total Plaque Risk Score (TPRS), are predictors of the ischemic events in the San Daniele study, a general population-based study of 1,348 subjects followed for 12 years in average. In the 171 subjects with at least one plaque at baseline, high TPRS was the most powerful independent predictor of cerebrovascular events, which occurred in 115 subjects. Addition of plaque characteristics significantly increased the area under the ROC curve (0.90 vs. 0.88, p = 0.04) versus the Framingham risk score alone. The TPRS is a potential new tool to improve the stroke risk prediction.

One year intermittent rifaximin plus fibre supplementation vs. fibre supplementation alone to prevent diverticulitis recurrence: A proof-of-concept study

BACKGROUND Evidence supporting appropriate medical therapy to prevent recurrence of colonic diverticulitis is limited. Our goal was to evaluate the potential of rifaximin given periodically in addition to fibre for the prophylaxis of recurrences. METHODS We conducted a multicentre, randomized, open controlled study in patients with a recent episode of colonic diverticulitis, currently in remission. Patients received 3.5 g of high-fibre supplementation b.d. with or without one week per month of the non-absorbable antibiotic rifaximin (400 mg b.d.) for 12months. Primary endpoint was recurrence of diverticulitis, encompassing acute symptomatic flare with or without complications, analyzed by multivariable logistic regression analysis and by Cox proportional hazard method. RESULTS After randomizing 165 patients, the study was interrupted since the recruitment rate was largely below the minimum anticipated, and the trial was switched from evidence-gathering to proof-of-concept. Recurrences occurred in 10.4% of patients given rifaximin plus fibres vs. 19.3% of patients receiving fibres alone. The logistic analysis adjusted for sex, age, illness duration, time from last episode, disease localization and centre recruitment rate, yielded a significant treatment effect (odds ratio 3.20; 95% confidence interval: 1.16-8.82; P=0.025). Patients with diverticulitis diagnosed since ≥1 year receiving rifaximin also had a lower incidence of recurrences (10%; 95% confidence interval: 2-47% vs. 67%; 95% confidence interval: 37-100%). Both treatments were safe. CONCLUSIONS This study represents a proof-of concept of the efficacy of cyclic rifaximin treatment, added to fibre supplements, to reduce the risk of recurrences of diverticulitis in patients in remission.

Age and origin of the FCMD 3′-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population

Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences within the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease known to be caused primarily by an ancient retrotransposal integration. By applying two methods for the study of linkage disequilibrium between flanking polymorphic markers and the disease locus, and of its decay over time, the age of the insertion mutation causing FCMD in Japanese patients is calculated to be approximately 102 generations (95% confidence interval: 86–117 g), or slightly less. The estimated age dates the most recent common ancestor of the mutation-bearing chromosomes back to the time (or a few centuries before) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandable in the context of Japan’s history and the founder effect consistent with the prevalent theory on the origins of the modern Japanese population.

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.