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The novel direct oral anticoagulants (DOAC) have been shown to be at least as effective as and safer than conventional anticoagulants for the initial and long-term treatment of venous thromboembolic disorders. However, the rate of post-thrombotic syndrome (PTS) in patients with deep-vein thrombosis (DVT) treated with the DOACs is unknown. With the adoption of the Villalta scale, we assessed the rate of PTS at the end of the follow-up period in a consecutive series of 309 outpatients with acute proximal DVT who had received at least 3 months of treatment with a DOAC and had been followed-up for up to 3 years. The rate of PTS development was compared with that recorded in a historical cohort of 1036 consecutive patients who had been treated with vitamin K antagonists (VKA) and had received a similar follow-up examination. Logistic regression analysis, including propensity scoring to adjust for differing probabilities of undergoing VKA/DOAC, was used to identify predictors of PTS. PTS developed in 87 patients (28.2%) treated with the DOACs (severe in 12), and in 443 patients (42.8%) treated with VKAs (severe in 61). After adjusting for estimated propensity score, age, gender, concomitant symptoms of pulmonary embolism, duration of anticoagulation and development of residual vein thrombosis, the risk of PTS in the DOAC-treated patients was reduced by 54% in comparison to patients treated with conventional anticoagulation (odds ratio 0.46; 95% CI 0.33 to 0.63). We conclude that in comparison to VKAs, the use of the direct oral anticoagulants has the potential to offer a more favorable prognosis in terms of PTS development.

Background & Aims: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting., Methods: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment., Results: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%)., Conclusions: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting., Lay Summary: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting., Methods: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment., Results: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m 2 , and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x10 3 /mm 3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes., Conclusions: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks., Lay Summary: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles., (Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Aims: Right bundle branch block (RBBB) typically presents with only delayed right ventricular activation. However, some patients with RBBB develop concomitant delayed left ventricular (LV) activation. Such patients may show a specific electrocardiographic (ECG) pattern resembling RBBB in the precordial leads in association with an insignificant S-wave in lateral limb leads (atypical RBBB). We therefore postulated that the ECG pattern of atypical RBBB might be able to identify a subgroup of patients likely to respond to cardiac resynchronization therapy (CRT). The purpose of this study was to assess the impact of RBBB ECG morphology on CRT response in patients with heart failure (HF)., Methods and Results: We evaluated the echocardiographic clinical response of 66 patients with RBBB treated with CRT and followed up for almost 2 years. The patients were divided electrocardiographically into 2 groups: 31 with typical RBBB and 35 with atypical RBBB. Responders were classified in terms of reduction in LV end-systolic volume index (ESVi) ≥ 15% or reduction in the New York Heart Association (NYHA) Class ≥ 1 or Packer score variation (NYHA response with no HF-related hospitalization events or death). The atypical RBBB group presented a longer LV activation time compared with the typical RBBB group (111.9 ± 17.6 vs. 73.2 ± 15.4 ms; P < 0.001). In the atypical and typical RBBB groups, respectively, 71.4% and 19.4% of patients were ESVi responders (P = 0.001) 74.3% and 32.3% were NYHA responders (P = 0.002); similarly, 71.4% and 29.0% of patients exhibited a 2-year Packer score of 0 (P = 0.002)., Conclusion: Patients with atypical RBBB, which is a pattern highly suggestive of concomitant delayed LV conduction, may show a satisfactory response to CRT.

Purpose: In order to increase the responder rate to CRT, stimulation of the left ventricular (LV) from multiple sites has been suggested as a promising alternative to standard biventricular pacing (BIV). The aim of the study was to compare, in a group of candidates for CRT, the effects of different pacing configurations-BIV, triple ventricular (TRIV) by means of two LV leads, multipoint (MPP), and multipoint plus a second LV lead (MPP + TRIV) pacing-on both hemodynamics and QRS duration., Methods: Fifteen patients (13 male) with permanent AF (mean age 76 ± 7 years; left ventricular ejection fraction 33 ± 7%; 7 with ischemic cardiomyopathy; mean QRS duration 178 ± 25 ms) were selected as candidates for CRT. Two LV leads were positioned in two different branches of the coronary sinus. Acute hemodynamic response was evaluated by means of a RADI pressure wire as the variation in LVdp/dtmax., Results: Per patient, 2.7 ± 0.7 veins and 5.2 ± 1.9 pacing sites were evaluated. From baseline values of 998 ± 186 mmHg/s, BIV, TRIV, MPP, and MPP-TRIV pacing increased LVdp/dtmax to 1200 ± 281 mmHg/s, 1226 ± 284 mmHg/s, 1274 ± 303 mmHg, and 1289 ± 298 mmHg, respectively (p < 0.001). Bonferroni post-hoc analysis showed significantly higher values during all pacing configurations in comparison with the baseline; moreover, higher values were recorded during MPP and MPP + TRIV than at the baseline or during BIV and also during MPP + TRIV than during TRIV. Mean QRS width decreased from 178 ± 25 ms at the baseline to 171 ± 21, 167 ± 20, 168 ± 20, and 164 ± 15 ms, during BIV, TRIV, MPP, and MPP-TRIV, respectively (p < 0.001)., Conclusions: In patients with AF, the acute response to CRT improves as the size of the early activated LV region increases.

Background & Aims: Direct-acting antiviral agents (DAAs) are safe and effective in patients with hepatitis C. Conflicting data were reported on the risk of hepatocellular carcinoma (HCC) during/after therapy with DAAs. The aim of this study was to evaluate the incidence of newly diagnosed HCC and associated risk factors in patients with advanced hepatitis C treated with DAAs., Methods: The study is based on the NAVIGATORE platform, a prospectively recording database of all patients with hepatitis C receiving DAAs in the Veneto region of Italy. The inclusion criteria were: fibrosis stage ≥F3. The exclusion criteria were: Child-Turcotte-Pugh (CTP)-C, liver transplantation before DAAs, history or presence of HCC, follow-up <4 weeks after starting DAAs. A total of 3,917 out of 4,234 consecutive patients were included, with a mean follow-up of 536.2 ± 197.6 days., Results: Overall, HCC was diagnosed in 55 patients. During the first year, HCC incidence was 0.46% (95% CI 0.12-1.17) in F3, 1.49% (1.03-2.08) in CTP-A and 3.61% (1.86-6.31) in CTP-B cirrhotics; in the second year, HCC incidences were 0%, 0.2%, and 0.69%, respectively. By multivariate analysis, HCC was significantly associated with an aspartate aminotransferase to platelet ratio ≥2.5 (hazard ratio [HR] 2.03; 95% CI 1.14-3.61; p = 0.016) and hepatitis B virus infection (HR 3.99; 1.24-12.91; p = 0.021). Failure to achieve a sustained virological response was strongly associated with development of HCC (HR 9.09; 5.2-16.1; p = 0.0001). A total of 29% of patients with HCC had an aggressive tumor, often seen in the early phase of treatment., Conclusions: These data, obtained in a large, prospective, population-based study, indicate that in patients with advanced hepatitis C receiving DAAs, the risk of "de novo" hepatocarcinoma during the first year is not higher, and might be lower, than that of untreated patients. The risk further declines thereafter. Early hepatocarcinoma appearance may reflect pre-existing, microscopic, undetectable tumors., Lay Summary: Hepatocellular carcinoma is one of the complications of hepatitis C related cirrhosis. Treating patients with advanced hepatitis C with the new interferon-free direct-acting antiviral agents has been associated with improvement in liver function and survival, while more conflicting data have been reported regarding the risk of hepatocellular carcinoma. We report the results of a prospective population study on the incidence of newly diagnosed hepatocellular carcinoma in patients with advanced hepatitis C treated with direct-acting antiviral agents, clearly indicating that the residual hepatocellular carcinoma risk is reduced and declines progressively with time after a sustained virological response. Development of a liver tumor during/after therapy was associated with known risk factors and with virological failure., (Copyright © 2018. Published by Elsevier B.V.)

Background: The association between venous and arterial thrombotic disorders is still unclear. We assessed the association between residual vein thrombosis (RVT) and subclinical atherosclerosis in a cohort of patients with unprovoked (or associated with weak risk factors) proximal deep-vein thrombosis (DVT)., Methods: In a multicenter cross-sectional study, consecutive patients over 40years free from atherosclerotic disorders received the ultrasound assessment of the leg vein system and that of carotid arteries approximately three months after an episode of proximal DVT. In each center the evaluation was done by two independent assessors. The presence of RVT was defined as the incompressibility of at least 4mm in either the popliteal or the common femoral vein, and that of subclinical atherosclerosis as the presence of increased (>0.9mm) intima-media tickness (IMT) and/or carotid plaques., Results: Out of 252 patients (mean age, 67; males, 53%; unprovoked, 77%), the presence of RVT was found in 139 (55.2%). An increased IMT was shown in 76 (54.7%) patients with and in 35 (31.0%) without RVT (p<0.001). At least one carotid plaque was found in 80 (57.6%) patients with and in 36 (31.9%) without RVT (p<0.001). After adjusting for the baseline characteristics, the odds ratio of subclinical atherosclerosis (increased IMT and/or carotid plaques) was 2.8 (95% CI, 1.6 to 4.7)., Conclusion: The ultrasound detection of RVT after an episode of proximal DVT that is either unprovoked or triggered by weak risk factors is associated with a higher prevalence of subclinical atherosclerosis. These findings may have implications for patient prognosis., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The recanalization rate in patients with deep venous thrombosis (DVT) of the legs treated with the direct oral anticoagulants (DOAC) is unknown., Methods: In an Italian cohort, we investigated the rate of residual vein thrombosis (RVT) after three and/or six months in 352 patients with proximal DVT who had been treated with the DOACs as a stand-alone therapy or lead-in parenteral anticoagulants, and compared it to that recorded in a historical cohort of 1094 patients in which vitamin K antagonists (VKAs) had been employed. In both cohorts, RVT was defined as the ultrasound persistence of thrombotic material resulting in a diameter of at least 4mm of incompressibility of the proximal veins., Results: RVT was detected in 143 patients treated with DOACs (41.2%) after three months and in 58 patients (21.1%) after six months; the corresponding figure in patients treated with conventional anticoagulation was 52.3% and 54.5%, respectively. After adjusting for the baseline characteristics, the odds ratio of RVT in patients treated with the DOACs as compared with those treated with conventional anticoagulation was 0.63 (95% CI, 0.48-0.81) after three months, and 0.17 (95% CI; 0.11-0.26) after six months., Conclusions: In patients with proximal DVT treated with the DOACs, the persistence of ultrasound detectable RVT is likely to occur less frequently than in patients treated with conventional anticoagulation. These results may have implications for the prognosis of patients with DVT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Estimating left ventricular electrical delay (Q-LV) from a 12-lead ECG may be important in evaluating cardiac resynchronization therapy (CRT)., Objective: The purpose of this study was to assess the impact of Q-LV interval on ECG configuration., Methods: One hundred ninety-two consecutive patients undergoing CRT implantation were divided electrocardiographically into 3 groups: left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific intraventricular conduction delay (IVCD). The IVCD group was further subdivided into 81 patients with left (L)-IVCD and 15 patients with right (R)-IVCD (resembling RBBB, but without S wave in leads I and aVL). The Q-LV interval in the different groups and the relationship between ECG parameters and the maximum Q-LV interval were analyzed., Results: Patients with LBBB presented a long Q-LV interval (147.7 ± 14.6 ms, all exceeding cutoff value of 110 ms), whereas RBBB patients presented a very short Q-LV interval (75.2 ± 16.3 ms, all <110 ms). Patients with an IVCD displayed a wide range of Q-LV intervals. In L-IVCD, mid-QRS notching/slurring showed the strongest correlation with a longer Q-LV interval, followed, in decreasing order, by QRS duration >150 ms and intrinsicoid deflection >60 ms. Isolated mid-QRS notching/slurring predicted Q-LV interval >110 ms in 68% of patients. The R-IVCD group presented an unexpectedly longer Q-LV interval (127.0 ± 12.5 ms; 13/15 patients had Q-LV >110 ms)., Conclusion: Patients with LBBB have a very prolonged Q-LV interval. Mid-QRS notching in lateral leads strongly predicts a longer Q-LV interval in L-IVCD patients. Patients with R-IVCD constitute a subgroup of patients with a long Q-LV interval., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Approximately one-third of the patients with heart failure (HF) treated with cardiac resynchronization therapy (CRT) fail to respond. Positioning the left ventricular (LV) pacing lead in the area of the latest electrical delay may improve the response to CRT. Multipoint pacing (MPP) of the LV has been shown to improve the acute hemodynamic response., Objective: The purpose of this study was to test the hypothesis that patients treated with MPP in whom LV pacing location is optimized have better long-term clinical outcomes than do patients treated with conventional CRT., Methods: We evaluated the echocardiographic and clinical response of 110 patients with HF treated for nearly 1 year with either conventional CRT (standard [STD] group, n = 54, 49%), CRT with hemodynamic and electrical optimization of the LV pacing site (optimized [OPT] group, n = 36, 33%), or OPT combined with MPP (OPT + MPP group, n = 20, 18%). Responders were classified in terms of reduction in end-systolic volume index ≥15%, reduction in New York Heart Association (NYHA) class ≥1, and Packer score variation (NYHA response with no HF-related hospitalization events or death)., Results: In STD, OPT, and OPT + MPP groups, 56%, 72%, and 90% of patients, respectively, were end-systolic volume index responders (P = .004) and 67%, 78%, and 95% were NYHA class responders (P = .012); 59%, 67%, and 90% of patients exhibited a 1-year Packer score of 0 (P = .018). These trends remained significant after adjustment for confounding factors by multivariate logistic analysis., Conclusion: Combining MPP with optimal positioning of the LV lead on the basis of electrical delay and hemodynamics enhances reverse remodeling and improves clinical outcomes beyond the effect due to conventional CRT., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Without thromboprophylaxis, knee arthroscopy (KA) carries a low to moderate risk of venous thromboembolism. Over 5 million arthroscopies are performed worldwide yearly. It was our study objective to assess the efficacy and safety of rivaroxaban for thromboprophylaxis after therapeutic KA. Patients undergoing KA in nine Italian teaching or community hospitals were allocated to once-daily rivaroxaban (10 mg) or placebo for seven days in a phase II, multicentre, double-blind, placebo-controlled randomised trial. The primary efficacy outcome was a composite of all-cause death, symptomatic thromboembolism and asymptomatic proximal DVT at three months; major bleeding represented the primary safety outcome. All patients underwent whole-leg ultrasonography at day 7(+1), or earlier if symptomatic. A total of 241 patients were randomised (122 rivaroxaban, 119 placebo), and 234 completed the study. The primary efficacy outcome occurred in 1/120 of the rivaroxaban group and in 7/114 of the placebo group (0.8 % vs 6.1 %, respectively, p=0.03; absolute risk difference, -5.3 %, 95 % CI, -11.4 to -0.8; crude relative risk 0.14, 95 % CI, 0.02 to 0.83; number-needed-to-treat=19). No major bleedings were observed. We found no association between different arthroscopic procedures and thrombotic events. Small sample size, high exclusion rate, and low number of anterior cruciate ligament reconstruction procedures are the main limitations of our study. In conclusion, a seven-day course of 10-mg rivaroxaban may be safely employed for thromboprophylaxis after KA. Whether prophylaxis after KA should be given to all patients, or to selected "high-risk" subjects, remains to be determined. A larger trial to verify our preliminary results is warranted.

Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis.

Aims: Right ventricular pacing adversely affects left atrial (LA) structure and function that may trigger atrial fibrillation (AF). This study compares the occurrence of persistent/permanent AF during long-term Hisian area (HA), right ventricular septal (RVS), and right ventricular apex (RVA) pacing in patients with complete/advanced atrioventricular block (AVB)., Methods and Results: We collected retrospective data from 477 consecutive patients who underwent pacemaker implantation for complete/advanced AVB. Ventricular pacing leads were located in the HA, RVS, and RVA in 148, 140, and 189 patients, respectively. The occurrence of persistent/permanent AF was observed in 114 (23.9%) patients (follow-up 58.5 ± 26.5 months). Hisian area groups presented a lower rate of AF occurrence (16.9%) compared with RVS and RVA groups (25.7 and 28.0%, respectively), P = 0.049. Cox's proportional hazard model was used to estimate HR. The risk of persistent/permanent AF was significantly lower in the patients paced from HA compared with those paced from RVA, HR = 0.28 (95% CI 0.16-0.48, P = 0.0001). The RVS and RVA pacing groups showed a similar AF risk: HR 1.04 (95% CI 0.66-1.64, P = 0.856). Other independent predictors of persistent/permanent AF occurrence included previous (before device implantation) paroxysmal AF (HR = 4.08; 95% CI 3.15-7.31, P = 0.0001), LA diameter, and age, whereas baseline bundle-branch block was associated with a lower risk of AF occurrence (HR = 0.56; 95% CI 0.35-0.81, P = 0.003)., Conclusions: HA pacing compared with RVA or RVS pacing seems to be associated with a lower risk of persistent/permanent AF occurrence. The risk of persistent/permanent AF was similar in the RVA vs. RVS groups., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Background: Response to cardiac resynchronization therapy (CRT) remains challenging. Pacing from multiple sites of the left ventricle (LV) has shown promising results., Objective: The purpose of this study was to systematically compare the acute hemodynamic effects of multipoint pacing (MPP) by means of a quadripolar lead with conventional biventricular (BiV) pacing., Methods: Twenty-nine patients (23 men; mean age 72 ± 12 years; LV ejection fraction 29% ± 7%; 15 with ischemic cardiomyopathy, 17 with left bundle branch block; mean QRS 183 ± 23 ms) underwent CRT implantation. Per patient, 3.2 ± 1.2 different veins and 6.3 ± 2.4 pacing sites were tested. LV electrical delay (Q-LV) was measured at each location, along with the increase in LV dP/dtmax (maximum rate of rise of LV pressure) obtained by BiV and MPP. The effect of MPP, by means of simultaneous pacing from distal and proximal dipoles, was investigated at all available sites., Results: Overall, 3.2 ± 1.2 different MPP measurements were collected per patient. When all sites were considered, LV dP/dtmax increased from 951 ± 193 mm Hg/s at baseline to 1144 ± 255 and 1178 ± 259 mm Hg/s on BiV and MPP, respectively. When the best site was considered, LV dP/dtmax increased from a baseline value of 942 ± 202 mm Hg/s to 1200 ± 267 mm Hg/s (BiV) and 1231 ± 267 mm Hg/s (MPP). The mean QRS duration at any site during MPP and conventional CRT was 171 ± 18 and 175 ± 16 ms (P = .003), respectively., Conclusion: Compared with BiV pacing at any LV site, MPP yielded a small but consistent increase in hemodynamic response. A correlation between the increase in hemodynamics and Q-LV on MPP was observed for all measurements, including those taken at the best and worst sites. The MPP-induced improvement in contractility was associated with significantly greater narrowing of the QRS complex than conventional BiV pacing., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

The impact of residual vein thrombosis (RVT) on the long-term outcome of patients with deep vein thrombosis (DVT) is unknown. We assessed the incidence of recurrent venous thromboembolism (VTE), postthrombotic syndrome (PTS), arterial thrombotic events, and cancer in patients with DVT with and without RVT. For this purpose, we evaluated up to 3 years 869 consecutive patients with acute proximal DVT who had conventional anticoagulation. RVT, defined as ultrasound incompressibility of at least 4 mm in the common femoral and/or the popliteal vein after 3 months, was detected in 429 (49.4%) patients, and was more likely in males (adjusted odds ratio [OR], 1.82; 95% confidence interval [CI], 1.37-2.04), in patients with previous VTE (OR, 1.64; 95% CI, 1.06-2.54), and in those with extensive thrombosis (OR, 3.58; 95% CI, 2.19-5.86). During the 3-year follow-up, recurrent VTE developed in 84 (19.6%) patients with RVT and 43 (9.8%) patients without RVT (adjusted hazard ratio [HR], 2.03; 95% CI, 1.40-2.94); PTS in 225 (52.4%) and 118 (26.8%), respectively (HR, 2.34; 95% CI, 1.87-2.93); arterial thrombosis in 29 (6.7%) and 14 (3.2%), respectively (HR, 2.05; 95% CI, 1.08-3.88); and cancer in 21 (4.9%) and 8 (1.8%), respectively (HR, 3.09; 95% CI, 1.31-7.28). In conclusion, in patients treated with vitamin K antagonists for prevention of recurrent VTE, RVT doubles the risk of recurrent VTE, PTS, arterial thrombosis, and cancer. Males, patients with previous VTE, and those with extensive thrombosis are independent risk factors of RVT development. Studies addressing the impact of the novel direct anticoagulants on the development of RVT as well as the long-term complications of DVT are needed., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Aims: Right ventricular apex (RVA) pacing has adverse effects on left atrial (LA) function and may contribute to atrial arrhythmias. The effects of Hisian area (HA) pacing on LA function are still lacking. The objective of this study is to assess the left ventricular (LV) electromechanical activation/relaxation, systolic (S), diastolic (D) phases, and their effects on LA function during pacing from HA and RVA., Methods and Results: Thirty-seven patients with normal cardiac function underwent permanent HA pacing. In all patients, a RVA backup lead was added. The patients first underwent 3 months of HA pacing, followed by 3 months of RVA pacing. After each 3-month period, we compared by echocardiography: S-D LV electromechanical delay (S-D EMD), S-D intra-LV dyssynchrony, LV S-D phases, and their function evaluated by myocardial performance index (MPI) and mitral annular tissue Doppler early diastolic velocity (E'), pulmonary arterial systolic pressure (PASP), and LA function (LA phasic volumes and their emptying fraction). Right ventricular apex compared with HA pacing increased S-D EMD (P < 0.001) and intra-LV dyssynchrony (P < 0.001). As a consequence, a significant longer LV isovolumetric contraction time (P < 0.001) and LV isovolumetric relaxation time (P = 0.05) were measured during RVA compared with HA pacing, whereas LV ejection time was shorter (P = 0.033). Moreover, HA pacing resulted in significantly better MPI (P = 0.039), higher value of E' (P = 0.049), and lower PASP (P < 0.001). Finally, RVA compared with HA pacing was associated to higher LA volumes pre-atrial contraction (P = 0.001) and minimal volume (P = 0.003) with reduction in passive emptying fraction (P < 0.001) and total emptying fraction (P = 0.005)., Conclusion: Hisian area compared with RVA pacing resulted in a more physiological LV electromechanical activation/relaxation and consequently better LA function., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Background: One of the reasons for patient nonresponse to cardiac resynchronization therapy is a suboptimal left ventricular (LV) pacing site. LV electric delay (Q-LV interval) has been indicated as a prognostic parameter of cardiac resynchronization therapy response. This study evaluates the LV delay for the optimization of the LV pacing site., Methods and Results: Thirty-two consecutive patients (23 men; mean age, 71±11 years; LV ejection fraction, 30±6%; 18 with ischemic cardiomyopathy; QRS, 181±25 ms; all mean±SD) underwent cardiac resynchronization therapy device implantation. All available tributary veins of the coronary sinus were tested, and the Q-LV interval was measured at each pacing site. The hemodynamic effects of pacing at different sites were evaluated by invasive measurement of LV dP/dtmax at baseline and during pacing. Overall, 2.9±0.8 different veins and 6.4±2.3 pacing sites were tested. In 31 of 32 (96.8%) patients, the highest LV dP/dtmax coincided with the maximum Q-LV interval. Q-LV interval correlated with the increase in LV dP/dtmax in all patients at each site (AR1 ρ=0.98; P<0.001). A Q-LV value >95 ms corresponded to a >10% in LV dP/dtmax. An inverse correlation between paced QRS duration and improvement in LV dP/dtmax was seen in 24 patients (75%)., Conclusions: Pacing the LV at the latest activated site is highly predictive of the maximum increase in contractility, expressed as LV dP/dtmax. A positive correlation between Q-LV interval and hemodynamic improvement was found in all patients at every pacing site, a value of 95 ms corresponding to an increase in LV dP/dtmax of ≥10%., (© 2014 American Heart Association, Inc.)

Aims: A short paced (p) QRS duration (d) can be a marker for selecting the most appropriate RV pacing site. Although this could be achieved by continual 12-Lead ECG monitoring, such a technique is not applicable during pacemaker (PM) implantation. The purpose of this study was to validate a method for identifying the optimal site for RV septum pacing using simple markers derived from few real-time ECG leads and fluoroscopy (F)., Methods and Results: An overall of 304 measurements of pQRSd in different RV sites was performed in 102 patients undergoing PM implant. In accordance with F position the lead placement was classified high, medium, and low septum. Paced electrocardiographic/fluoroscopic parameters (q-wave/negative QRS in lead I, notching in limb leads, R/S wave in lead II, QRS precordial leads transition, and F septal segments pacing site) were analyzed to predict short pQRSd (≤ 160 ms). Logistic regression analysis showed that pQRSd > 160 ms was predicted by presence of pQRS notching in limb leads (OR = 3.24, p < 0.001), and with negative amplitude of QRS in lead II (OR = 2.53, p = 0.03). Short pQRSd (≤ 160 ms) was observed with mid F position (OR = 0.31, p < 0.001) and with the presence of a q-wave/negative QRS in lead I., Conclusion: In RV septum pacing, simple QRS markers of few limb leads (lead I/II) added to F position are usefull to identifying the optimal site to place the RV lead.

Objective: The goal of this study was to evaluate the role of intraoperative aneurysm sac embolization during endovascular aneurysm repair (EVAR) using a standard dose of coils and fibrin glue in the prevention of type II endoleak (EII)., Methods: Two groups were compared: 83 patients underwent standard EVAR during the period 2008-2009 (group A) and 79 patients underwent EVAR during the period 2010-2011 (group B). Computed tomography scans were evaluated with Osirix Pro 4.0 software to obtain aneurysm sac volume. EII rates at the first computed tomography scan follow-up, as well as midterm freedom from EII and freedom from related reintervention, were compared. Preoperative number of patent aortic side branches (inferior mesenteric artery, lumbar arteries, accessory renal arteries), sac thrombus, and sac volume were evaluated for their association with EII in the two groups using multiple logistic regressions., Results: Patient characteristics, Society for Vascular Surgery comorbidity scores (0.85 ± 0.44 vs 0.82 ± 0.46; P = .96), and operative time (185 ± 52 vs 179 ± 49; P = .92) were similar for groups A and B. The first computed tomography scan (≤3 months) revealed a significantly larger number of EIIs in group A than in group B (23% vs 10%; P = .02). Spontaneous EII resolution occurred in 65% of patients in group A and in 79% in group B (P = 1.0), whereas sac volume increased in 25% and 10% (P = .63) of cases, respectively. At 18 months (range, 6 months to 4.4 years), overall mean differences in sac volume shrinkage (27 ± 12 cm(3) vs 25 ± 12 cm(3); P = .19) and freedom from EII (92% vs 96%; P = .33) were similar, whereas freedom from reintervention was significantly lower in group A (93% vs 99%; P = .03) than in group B. Multivariate analysis showed preoperative aneurysm sac volume >125 cm(3) to be the only independent significant predictor of EII (odds ratio, 4.0; 95% confidence interval, 1.5-10.5; P = .005)., Conclusions: Although further confirmatory studies are needed, sac embolization during EVAR may be a valid approach to preventing EII and its complications during short- and midterm follow-up. More aggressive intraoperative embolization should be considered for patients with a preoperative aneurysm sac volume >125 cm(3)., (Copyright © 2013 Society for Vascular Surgery. All rights reserved.)

While there is conclusive evidence that aspirin plays a role in reducing the risk of clinically relevant venous thromboembolism (VTE) arising in a number of surgical and non-surgical situations at risk, little is known of the potential of aspirin for the long/term prevention of recurrent VTE. In two recent multicentre, double-blind studies (WARFASA and ASPIRE), the efficacy and safety of a low dose of aspirin (100 mg per day) were assessed in patients with unprovoked VTE who had completed an initial period of conventional treatment with vitamin K antagonists. The two studies used identical aspirin regimens and had similar enrollment criteria and outcome measures. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90) and a 34% reduction in the rate of major vascular events (HR, 0.66; 95% CI, 0.51-0.86). Moreover, these benefits were achieved with a low risk of bleeding. As patients with previous symptomatic atherosclerosis were not enrolled in these two studies, whether these results apply also to this category of patients is uncertain. We recently had the opportunity to review the clinical charts of 1919 consecutive patients presented with a first episode of VTE, which was either unprovoked or triggered by transient risk factors, and were followed up for an average period of four years after discontinuing anticoagulation. The rate of recurrent VTE in the 256 patients with a history of symptomatic atherosclerosis who had been given 80-160 mg of aspirin once daily (17.2%) did not differ from that (19.9%) observed in those without atherosclerosis who were left without any antithrombotic treatments. The implication of this observation is that whenever patients with symptomatic atherosclerosis are deemed to require long-term protection against recurrent VTE, they are unlikely to benefit from (resuming) aspirin. Conversely, aspirin in low doses offers an appealing, safe and highly cost-effective option for the long-term prevention of recurrent events in patients with unprovoked VTE who are free from symptomatic atherosclerotic lesions.

Unlabelled: Treatment with pegylated interferon alpha (PegIFNα) and ribavirin is still regarded as the standard of care for chronic hepatitis C virus (HCV). Retinopathy has been occasionally described but prospective, longitudinal data are lacking. We investigated the frequency and clinical significance of retinopathy during therapy with PegIFNα and ribavirin in 97 consecutive HCV patients. In all, 54 (55.7%) and 43 (44.3%) patients were treated with PegIFNα 2a and PegIFNα 2b, respectively. Ophthalmologic examination was performed before therapy (baseline), at 3 and 6 months (3T and 6T, respectively) of therapy, and 3 months after the end of therapy (3ET). All patients underwent the baseline and 3T examination, 95.9% and 90.7% of patients underwent 6T and 3ET examination, respectively. Overall, 30.9% of patients developed retinopathy, as defined by the presence of cotton wool spots and/or retinal hemorrhages. Variables significantly associated with retinopathy during treatment were age (P = 0.004), metabolic syndrome (P = 0.05), hypertension (P < 0.0001), cryoglobulinemia (P = 0.05), and preexisting intraocular lesions at baseline (P = 0.01). By multivariate analysis, the only variable independently associated with PegIFNα-associated retinopathy was hypertension (hazard ratio [HR] = 4.99, 95% confidence interval [CI] 2.29-10.89). The frequency of retinopathy was significantly higher in hypertensive patients versus those without hypertension at all timepoints (18.5% versus 5.7% at baseline, P = 0.05; 48.1% versus 15.7% at 3T, P = 0.0009; 68.0% versus 19.1% at 6T, P < 0.0001; 32.0% versus 6.2%, P = 0.0005 at 3ET). In one (1.1%) hypertensive patient, who developed bilateral branch retinal vein occlusion at 6T, the therapy was discontinued. A cost analysis showed that screening for PegIFNα-associated retinopathy was cost-effective as compared with thyroid-stimulating hormone screening., Conclusion: Retinopathy is frequent during treatment with PegIFNα and ribavirin, especially in hypertensive patients, who may develop serious complications. Screening for PegIFNα-associated retinopathy should be recommended for HCV patients with hypertension., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

Background: Prophylaxis of venous thromboembolism (VTE) in hospitalized medical patients is largely underused. We sought to assess the value of a simple risk assessment model (RAM) for the identification of patients at risk of VTE., Methods: In a prospective cohort study, 1180 consecutive patients admitted to a department of internal medicine in a 2-year period were classified as having a high or low risk of VTE according to a predefined RAM. They were followed-up for up to 90 days to assess the occurrence of symptomatic VTE complications. The primary study outcome was to assess the adjusted hazard ratio (HR) of VTE in high-risk patients who had adequate in-hospital thromboprophylaxis in comparison with those who did not, and that of VTE in the latter group in comparison with low-risk patients., Results: Four hundred and sixty-nine patients (39.7%) were labelled as having a high risk of thrombosis. VTE developed in four of the 186 (2.2%) who received thromboprophylaxis, and in 31 of the 283 (11.0%) who did not (HR of VTE, 0.13; 95% CI, 0.04-0.40). VTE developed also in two of the 711 (0.3%) low-risk patients (HR of VTE in high-risk patients without prophylaxis as compared with low-risk patients, 32.0; 95% CI, 4.1-251.0). Bleeding occurred in three of the 186 (1.6%) high-risk patients who had thromboprophylaxis., Conclusions: Our RAM can help discriminate between medical patients at high and low risk of VTE. The adoption of adequate thromboprophylaxis in high-risk patients during hospitalization leads to longstanding protection against thromboembolic events with a low risk of bleeding., (© 2010 International Society on Thrombosis and Haemostasis.)

Background & Aims: Preliminary data suggest that non-invasive methods could be useful to assess presence of oesophageal varices (OV) in cirrhotic patients. We aimed to further investigate simple serum non-invasive markers for diagnosing and grading OV., Methods: A retrospective set of 510 cirrhotics and a prospective set of 110 cirrhotics were enrolled consecutively in five centers. Platelets, AST-to-ALT ratio, AST-to-platelet-ratio index, Forns' index, Lok index, Fib-4, and Fibroindex were measured within 2 months from upper endoscopy, taken as a gold standard. Performance was expressed as sensitivity, specificity, positive, and negative predictive values (PPV, NPV), accuracy, and area under the curve (AUC)., Results: A combination of Lok index (cutoff=1.5) and Forns' index (cutoff=8.8) had 0.80 AUC (0.76-0.84, 95% CI), and high NPV (>90%) to exclude clinically relevant OV, defined as large OV or small OV with red signs or in Child-Pugh C cirrhosis. By applying this combination, upper endoscopy would have been avoided in 1/3 of our cirrhotics. Large OV could be excluded with 96% NPV by Lok index (cutoff=1.5). A combination of Lok index (cutoff=0.9) and Forns' index (cutoff=8.5) predicted presence of any grade OV with good performance: 0.82 AUC (0.76-0.88, 95% CI), 88% PPV., Conclusions: Serum non-invasive markers may be useful as a first line tool to identify cirrhotic patients in which the risk of clinically relevant OV is trivial, and to reduce the number of upper endoscopies. However, we are still far from the possibility of replacing upper endoscopy by simple serum non-invasive markers in the vast majority of patients., (Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Insulin resistance (IR) reduces response to pegylated-interferon (PEG-IFN)/ribavirin in chronic hepatitis C (CHC), but the mechanisms are still undefined. We examined the relationship between baseline insulin levels, the main component affecting homeostasis model of assessment - insulin resistance (HOMA-IR) for assessment of IR in non-diabetic patients, and the 'acute' virological response to PEG-IFN measured 24 h after the first injection and taken as correlate of intracellular interferon signalling. In 62 patients treated with PEG-IFN/Ribavirin, serum insulin and HOMA-IR were assessed at baseline, while hepatitis C virus (HCV)-RNA was measured at baseline and 24 h, 1, 2, 4 and 12 weeks after treatment initiation. Sustained virological response was examined 24 weeks after therapy discontinuation. Mean baseline insulin was 11.52 +/- 8.51 U/L and mean HOMA-IR was 2.65 +/- 2.01 both being significantly higher with advanced liver fibrosis. Hepatitis C virus-RNA decay observed 24 h after the first injection of PEG-IFN was significantly lower (0.7 +/- 0.8 log) in patients with HOMA > or =3 compared with those with HOMA <3 (1.7 +/- 0.8, P = 0.001). A highly significant (r = -0.42) inverse correlation was observed between baseline insulin levels and the 24-h HCV-RNA decay. The difference in early viral kinetics between patients with HOMA > or =3 or <3 resulted in a significant difference in the percentage of patients achieving rapid (week 4) and sustained virological response. Multivariate analysis, inclusive of patient age, HCV genotype and fibrosis stage, identified baseline insulin levels as the main independent variable affecting the 24-h response to PEG-IFN. Hyperinsulinaemia reduces the cellular response to Pegylated-interferon in CHC with IR. Strategies to reduce insulin levels before initiation of treatment should be pursued to improve efficacy of anti-viral treatment.

Background: The right ventricular septum (RVS) and Hisian area (HA) are considered more "physiological" pacing sites than right ventricular apex (RVA). Studies comparing RVS to RVA sites have produced controversial results. There are no data about variability of electromechanical activation obtained by an approach using fluoroscopy and electrophysiological markers. This study compared the variability of left ventricular (LV) electromechanical activation in patients undergoing short-term RVA and RVS with that measured during HA pacing based on fluoroscopy and electrophysiological markers., Methods: Tissue Doppler echocardiography was performed in 142 patients before and after RVA (54), RVS (44), and HA (44) pacing. Electromechanical activation was assessed by: (1) electromechanical latency (EML)-interval between QRS onset and mechanical activation of basal LV; (2) intra-LV dyssynchrony (intra-LV)-interval between earliest to the latest LV basal motion. The intra- and interpatients variability among pacing groups were assessed., Results: Pacing from RVA showed longer EML and higher degree of intra-LV than RVS and HA pacing. RVA and RVS showed a higher variability than HA pacing with regard to intrapatient changes of EML (RVA vs RVS, P = 0.4; RVS vs HA, P = 0.01, RVA vs HA, P = 0.0002) and intra-LV (RVA vs RVS, P = 0.2; RVS vs HA, P = 0.04; RVA vs HA, P = 0.005). Similar results were found in interpatients variability from paced-values., Conclusions: RVA and RVS pacing produce a variable effect on LV electromechanical activation that is significantly more pronounced than HA pacing. A pacing site such as HA selected by fluoroscopic and electrophysiological markers maintains baseline and homogeneous LV activation pattern.

In absence of prophylaxis, the incidence of deep vein thrombosis after knee arthroscopy is reported to be as high as 18%. Recommendations for thromboprophylaxis after knee arthroscopy have actually been updated. The results of the largest randomized clinical trial (KANT study) in this setting are reported together with a review of the literature.

The aim of the study was to determine variables that could be used to predict survival in patients with ruptured abdominal aortic aneurysm (RAAA) and to assess the accuracy of the Glasgow Aneurysm Score (GAS) and the Acute Physiology Chronic Health Evaluation II (APACHE-II). From January 1998 to July 2006, 103 patients underwent operations for RAAA. For each patient, 44 variables were retrospectively recorded in a database. Data were analyzed with univariate and multivariate methods. In the univariate analysis significant predictors of death were hypotension (p=0.001), preexisting peripheral vascular disease (p<0.001), renal insufficiency (p=0.037), chronic obstructive pulmonary disease (p=0.028), level of HCO(3)(-) (p<0.001), intraperitoneal rupture (p=0.001), blood transfused (p<0.001), cardiac complications (p<0.001), and APACHE-II score (p=0.001). Multivariate analysis confirmed statistical significance for coexisting peripheral vascular disease (p<0.001), diastolic blood pressure at admission <60 mm Hg (p=0.039), APACHE-II score >18.5 (p=0.025), HCO(3)(-) <21 mg/dL (p<0.001), and intraperitoneal rupture of the aneurysm (p=0.011) as predictors of death. Results of the study suggested that different factors can be helpful in identifying those patients whose operative risk is prohibitive. APACHE-II, contrary to GAS, is an accurate system to predict postoperative death after repair for RAAA.

Objectives: Evaluation of left ventricular (LV) dyssynchrony in patients undergoing short-term right ventricular apical (RVA) pacing and correlation with baseline echocardiographic and clinical characteristics., Background: RVA pacing causes abnormal ventricular depolarization that may lead to mechanical LV dyssynchrony. The relationships between pacing-induced LV dyssynchrony and baseline echocardiographic and clinical variables have not been fully clarified., Methods: Tissue Doppler echocardiography was performed in 153 patients before and after RVA pacing. LV dyssynchrony was measured by the time between the shortest and longest electromechanical delays in the five basal LV segments (intra-LV). The prevalence and degree of LV dyssynchrony after RVA pacing was evaluated in three groups: baseline LV ejection fraction (LVEF) <35%, 35-55%, and >or=55%. The intrapatient effect of RVA pacing was determined as the percent increase in intra-LV value (Deltaintra-LV%). The pacing-induced intra-LV was correlated with baseline variables., Results: The prevalence and degree of LV dyssynchrony after RVA pacing was significantly higher in patients with lower LVEF (P < 0.001). DeltaIntra-LV% was inversely correlated with baseline intra-LV and LVEF (B =-2.6, B =-4.2, P < 0.001). Baseline intra-LV and LV end-systolic volume correlated positively with intra-LV after RVA pacing (B = 0.49, B = 0.6, P < 0.001), whereas LVEF showed an inverse correlation., Conclusions: The degree of LV dyssynchrony induced by RVA is variable. Patients with higher baseline LV dyssynchrony, more dilated LV, and more depressed LVEF showed a higher degree of LV dyssynchrony during pacing. These findings may assume importance in predicting the risk of heart failure in pacemaker patients.

Context: Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies., Objective: To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities., Design, Setting, and Patients: A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007., Main Outcome Measure: Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup., Results: Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%)., Conclusion: The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities., Trial Registration: clinicaltrials.gov Identifier: NCT00353093.

Background: B-type natriuretic peptide is the most powerful predictor of long term prognosis in patients hospitalised with heart failure. On an outsetting basis, a decrease in B-type natriuretic peptide levels is associated to a decrease in event rate for outpatients managed using the neuro-hormone levels as the target in heart failure therapy. We have retrospectively checked whether the addition of pre-discharge B-type natriuretic peptide levels to a clinical-instrumental decisional score for discharge decision in patients admitted for heart failure reduced readmission rate for heart failure and related cost., Methods: We studied two series of consecutive patients admitted to the Heart Failure Unit due to acute heart failure as a main diagnosis. One-hundred and forty-nine patients discharged on the basis of the sole clinical acumen were compared to one hundred and sixty-six subjects discharged adding B-type natriuretic peptide levels to the decisional score., Results: During a six-month follow-up period, there were 52 readmissions (35%) among the clinical group (n=149) compared with 38 (23%) readmissions in the B-type natriuretic peptide group (n=166) (chi(2)=5.5; P=0.02). Survival did not differ between groups (87%). Changes in B-type natriuretic peptide values were correlated to clinical events: a B-type natriuretic peptide value on discharge of < or =250 pg/ml or a reduction of > or =30% in B-type natriuretic peptide values predicted a 23% event rate (death, plus readmission for heart failure), whereas a far higher percentage (71%) were observed in the remaining patients (chi(2)=32.7; P=0.001). Likewise, the overall costs of care were lower (-7%) in the B-type natriuretic peptide group: 2.781+/-923 vs 2.978+/-1.057 euros per patient respectively., Conclusions: our study suggest that the addition of pre-discharge B-type natriuretic peptide levels to a clinical-instrumental decisional score for discharge decision in patients admitted for heart failure may contribute to reduce the number of readmissions and related cost.

Objective: Plasma brain natriuretic peptide (BNP) is an important parameter of severity in congestive heart failure (CHF). We analyzed if BNP might stratify 6-month clinical outcome in outpatients with CHF with restrictive mitral filling pattern., Methods: All subjects with New York Heart Association (NYHA) class II to IV and restrictive filling pattern were enrolled at hospital discharge after an acute decompensation. NYHA class, BNP, and echocardiogram for the evaluation of left ventricular ejection fraction (LVEF) and diastolic function were analyzed. Death and hospital readmission for CHF were the clinical events observed., Results: A total of 250 patients (66% were male, mean age 73 years) were enrolled. The mean NYHA class was 2.5 +/- 0.6, LVEF was 38% +/- 15%, and mean deceleration time was 120 +/- 16 ms. The mean BNP was 643 +/- 566 pg/mL. During the 6-month follow-up, 35 patients (14%) died and 106 patients (42.4%) were readmitted for CHF (event group); in 109 patients (43.6%) no events were observed (no-event group). Higher NYHA class (2.7 +/- 0.6 vs 2.4 +/- 0.6, P = .001) and reduced LVEF (34% +/- 13% vs 42% +/- 17%, P = .01) but similar deceleration time (119 +/- 16 ms vs 122 +/- 17 ms, P = not significant) were observed in the event group. A higher level of mean BNP (833 +/- 604 pg/mL vs 397 +/- 396 pg/mL, P = .01) was recorded in the event group. The multivariate Cox analysis confirmed that LVEF (P = .04), NYHA class (P = .02), and plasma BNP (P = .0001) were associated with adverse short-term clinical outcome., Conclusion: Patients with CHF with a restrictive diastolic pattern had poor short-term clinical outcome. NYHA class and LVEF at discharge might predict cardiovascular events, but plasma BNP proved to be the strongest predictor.

Background: Congestive heart failure (HF) is one of the most important cause of hospitalizations and is associated with high cost. Despite a consistent body of data demonstrating the benefits of drug therapy in HF, persistently high rates of readmission, especially within six months of discharge, continue to be documented. Neurohormonal activation characterizes the disease; plasma brain natriuretic peptide (BNP), is correlated with the severity of left ventricular dysfunction and relates to outcome., Objective: The aim of the study was to evaluate if plasma levels of BNP would provide an index to guide drug treatment and to predict medium-term prognosis in HF patients (pts) after hospital discharge., Methods and Results: We evaluated 200 consecutive pts (age 77 +/- 10 (35-96) years, 49% male versus 51% female) hospitalized for HF (DRG 127). Standard echocardiography was performed and left ventricular systolic/diastolic function was assessed; plasma BNP levels were measured with a rapid point-of-care assay (Triage BNP Test, Biosite Inc, San Diego, CA) on days 1 and after initial treatment. Using a cut-off of 240 pg/ml and/or changes in plasma BNP (days 2-3 after admission), 2 groups were identified: the low BNP group-responders (n = 68, BNP < 240 pg/ml and/or > or = 30% reduction) and the high BNP group-non responders (n = 132, BNP > or = 240 pg/ml and/or < 30% reduction). The high BNP group showed a different pattern of clinical variables according to the severity of the disease New York Heart Association (NYHA) functional class, left ventricular ejection fraction, ischemic etiology and age. A sustained elevation of plasma BNP (> 240 pg/mL) indicated the presence of a clinical unstable condition requiring further intervention whereas pts with low BNP values were discharged after 24 hours. During a mean follow-up period of 3 months, there were 62 cardiac events, including 15 cardiac deaths, 22 readmissions for worsening heart failure and 25 clinical decompensation requiring diuretic treatment. The incidence of clinical events was significantly greater in pts with higher levels of BNP (admission and discharge) than in those with lower levels (42% vs. 10%) and plasma values > 500 pg/ml identified a subgroup at high risk of death., Conclusions: The influence of BNP in the clinical course and prognosis of patients hospitalized for HF has not been studied. After initial treatment pts need to be risk stratified by means of the BNP test, to guide further management and to identify subjects with poor prognosis. An aggressive therapeutic and follow-up strategy may be justified for pts with high BNP levels and/or no changes after hospital admission for worsening HF. The changes in plasma BNP level at discharge were significantly related to cardiac events.

Activation of telomerase reverse transcriptase (hTERT) is essential for unlimited cell growth and plays a critical role in tumorigenesis. We investigated hTERT gene expression in 134 B-cell chronic lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression). Real-time PCR assays to quantify either all hTERT transcripts (AT) or only the full length (FL) transcript encoding the functional protein were developed. hTERT-AT levels strongly correlated with hTERT-FT levels (r=0.743, P<0.0001); both inversely correlated with the percentage of IgVH mutation (P<0.005) and were significantly higher in unmutated than in mutated cases (P=0.004 and P=0.001, respectively). The hTERT values which best discriminated between the unmutated and mutated IgVH cases were 150 and 40 copies for hTERT-AT and hTERT-FL, respectively. Using these cut-off values, there was a significant difference in the survival of patients with high or low hTERT levels (P<0.0001). Unmutated cases with low hTERT levels had an overall survival close to mutated cases with high hTERT levels. Thus, this work identifies hTERT-RNA level as a new prognostic marker in B-CLL, and may be used to identify previously unrecognized patient groups with the same IgVH mutation status and different disease outcomes.

Using polymerase chain reaction (PCR)-based sequence-specific primers, the killer immunoglobulin-like receptor (KIR) genotypes of 35 patients with natural killer (NK)-type lymphoproliferative disease of granular lymphocytes and of 50 normal subjects were investigated to evaluate whether genes coding for activating KIRs were more frequently detected in patients with NK-lymphoproliferative disease of granular lymphocytes (LDGL). Genotype frequency indicated that the most frequently found gene content was eight genes in controls and 14 in patients (P<0.05). The KIR genotype analysis revealed that patient and, surprisingly, control KIR genotypes preferentially consisted of type B haplotypes characterized by the presence of multiple-activating KIRs. Evidence was also provided that the same KIR genotype was shared by a variable number of patients. Interestingly, the recurrent genotypes observed in the patient group were not found in controls. Concerning inhibitory genes, KIR2DL5a and 2DL5b were more frequently detected in patients than in controls (P<0.01), likely representing a discrete feature of the genetic repertoire of the patients. KIR gene repertoire analysis in patients suggests that the susceptibility to NK-LDGL might be related to the presence of activating KIR genes and supports the concept that these receptors may be involved in the priming of granular lymphocytes (GL) proliferation. Population analysis might disclose a genetic background predisposing to this disease.

Background: The early identification of patients at risk for the development of clinical heart failure (HF) is a new challenge in an effort to improve outcomes., Methods: We prospectively evaluated whether the combination of brain natriuretic peptide (BNP) measurements (Triage BNP test, Biosite Diagnostics) and echocardiography would effectively stratify patients with new symptoms in a cost-effective HF program aimed at early diagnosis of mild HF. A total of 252 patients were referred by 100 general practitioners., Results: Among the study population, the median BNP value was 78 ng/L (range, 5-1491 ng/L). BNP concentrations were lower among patients without heart disease [median 15 ng/L (range, 5-167 ng/L); n = 96] than among patients with confirmed HF [median, 165 ng/L (22-1491 ng/L); n = 157; Mann-Whitney U-test, 12.3; P <0.001]. Patients were grouped into diastolic dysfunction [BNP, 195 (223) ng/L], systolic dysfunction [BNP, 290 (394) ng/L], and both systolic and diastolic dysfunction [BNP, 776 (506) ng/L]. In this model, a cutoff value of 50 ng/L BNP increases the diagnostic accuracy in predicting mild HF, avoiding 41 echocardiograms per 100 patients studied, with a net saving of 14% of total costs., Conclusions: Blood BNP concentrations, in a cost effective targeted screening, can play an important role in diagnosing mild HF and stratifying patients into risk groups of cardiac dysfunction.

In women diagnosed as having category I primary obstetric antiphospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-human beta2-Glycoprotein I (abeta2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis. All the women were aCL and abeta2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR = 122.5, 95% CI 16-957, p < 0.001). They also had an increased rate of late pregnancy loss (OR = 16.2, 95%CI 0.9-292, p = 0.01), and a higher IgG abeta2GPI titer at diagnosis (median, 25(th) and 75(th) percentile were 118, 37-962, vs. 23, 18-32, respectively, p < 0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/ or previous thromboembolism (OR = 57.5, 95% CI 2.7-1160, p = 0.0004) which were the only independent predictors of TE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR = 34.4, 95% CI 3.5-335.1, p = 0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category I, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboembolism predict new TE events and new unsuccessful pregnancies.

To examine the prognostic role of predischarge B-type natriuretic peptide (BNP) levels in elderly patients admitted to the hospital due to cardiogenic pulmonary edema, 203 patients consecutively admitted to the Heart Failure Unit of the Cardiology Department were retrospectively evaluated. The primary clinical end point selected was a combination of: 1) deaths; plus 2) readmissions to the hospital for heart failure in the 6 months after discharge. Thirty-one deaths (15.3%) and 44 readmissions for heart failure (21.7%) were recorded. Cox multivariate regression analysis confirmed that BNP cutoff values (identified on receiver-operated curve analysis) are the most accurate predictor of events. Hazard ratios (HRs) increased from the lowest, for BNP < or = 200 pg/mL (HR=1), through BNP 201-499 pg/mL (HR=2.3200; p=0.0174), to the highest, for BNP > or = 500 pg/mL (HR=3.6233; p=0.0009). This study demonstrates that BNP is useful in predischarge risk stratification of elderly patients with cardiogenic pulmonary edema.

The natural history of chronic hepatitis C presenting with no/minimal liver fibrosis is uncertain with controversies on risk of progression and need for antiviral treatment. We studied rates and determinants of fibrosis progression in initially mild chronic hepatitis C. One hundred and six patients (mean age 41.65 +/- 12.83 years) with chronic hepatitis C virus infection and no/minimal fibrosis in the initial liver biopsy (F0/F1 by METAVIR score) were followed prospectively while untreated with repeated biopsy after 5 or more years (mean interval 7.8 +/- 1.51 years). Patients showing fibrosis progression were compared with nonprogressors for baseline and follow-up parameters. Sixty-four patients (60.4%) showed fibrosis progression including 13 of 27 (49%) with F0 and 51 of 79 (65%) with F1. Progression to F3 or cirrhosis was seen in 36% of those with F1 initially. Fibrosis progression (DeltaF/year) was associated with age (P < 0.0001), baseline and follow-up alanine aminotransferase (ALT) (P = 0.005), histological activity (P = 0.004) and steatosis (P = 0.002) in the initial biopsy and use of alcohol (P = 0.008). Thus liver fibrosis progression occurs in two-thirds of patients with initially mild chronic hepatitis C within 5-10 years and advanced fibrosis/cirrhosis develops in one-third of those with F1 initially. Fibrosis is facilitated by older age and alcohol and associated with inflammatory activity and ALT levels. Antiviral therapy should be considered in mild chronic hepatitis C.

Background/aims: In chronic hepatitis C, biopsy is the gold standard for assessment of liver fibrosis. Non-invasive markers have been proposed but their use is limited by diagnostic accuracy. Our aim was to increase the diagnostic performance of non-invasive markers of liver fibrosis by combining them in sequential algorithms., Methods: One hundred and ninety patients with chronic hepatitis C were evaluated for AST to platelets ratio (APRI), Forns' index and Fibrotest at the time of liver biopsy and stepwise combination algorithms were developed and validated prospectively in 100 additional patients., Results: Three algorithms were developed: (1) significant fibrosis (F>or=2 by METAVIR) was identified with high diagnostic performance (>94% accuracy) using APRI as screening test, followed by Fibrotest in APRI non-classified cases and restricting liver biopsy to patients classified F0-F1 by non-invasive tests. (2) A slightly modified algorithm had similar performance when applied to hepatitis C carriers with normal ALT. (3) Identification of cirrhosis (95% accuracy) was achieved using a dedicated algorithm with different cut-off, reducing by 60-70% the liver biopsies needed., Conclusions: Stepwise combination of non-invasive markers of liver fibrosis improves the diagnostic performance in chronic hepatitis C. Need for liver biopsy is reduced by 50-70% but cannot be completely avoided.

Heart failure is a prominent problem of public health, requiring innovating methods of health services organization. Nevertheless, data are still not available on prevalence, hospitalization rate, adherence to Guidelines and social costs in the general Italian population. The necessity to identifying patients with heart failure derives from the efficacy of new therapeutic interventions in reducing morbidity and mortality. In this study we aimed to identify, in a subset of the Eastern Veneto population, patients with heart failure through a pharmacologic-epidemiologic survey. The study was divided in 5 phases: (1) identification of patients on furosemide in the year 2000 in the ASL 10 of Eastern Veneto general population, through an analysis of a specific pharmaceutic service database; (2) definition of the actual prevalence of heart failure in a casual sample of these patients, through data base belonging to general practitioners, cardiologists, or others. Diagnosis was based on the following criteria: (a) previous diagnosis of heart failure; (b) previous hospitalization for heart failure; (c) clinical evidence, with echocardiographic control in unclear cases; (3) survey of hospitalizations; (4) evaluation of adhesion to guidelines, through both databases and questionnaires; (5) analysis of the social costs of the disease, with a retrospective "bottom up" approach. From a total population of 198,000 subjects, we identified 4502 patients on furosemide. In a casual sample of 10,661 subjects we defined a prevalence of heart failure in Eastern Veneto of 1.1%, that increased to 7.1% in octagenarians. The prescription of life saving drugs was satisfactory, while rather poor was the indication to echocardiography and to cardiologic consultation. Hospitalization rate for DRG 127 was low: 2.1/1000 inhabitants/year in the general population and 12.5 /1000 inhabitants/year in patients >70 years of age. Yearly mortality was 10.3%. Social costs were elevated (15.394 Euros/patient/year), due to a relevant sanitary component (hospital 53%, drugs 28%) and particularly a to an indirect cost component. In conclusion, the assumption of furosemide lends itself as a good marker for identifying patients with heart failure. Patient identification is simple, cheap and cost-efficient, and can be easily reproduced in other regional areas.