Pain management in internal medicine and effects of a standardised educational intervention: the FADOI-DOMINO study.

PURPOSE: Few real-world data are available on the frequency and management of pain in Internal Medicine (IM). Aims of our study were to assess the prevalence of pain in IM, and to evaluate the effects on pain management of a standardised educational programme. MATERIALS AND METHODS: The study was performed in 26 IM Units in Italy, with two cross-sectional surveys (PRE phase and POST phase) interspersed with an educational programme. In PRE phase each Centre reviewed the hospital charts of the last 100 consecutive patients hospitalised for any cause. An educational programme was conducted in each Centre by means of the 'outreach visit', a face-to-face meeting between health personnel and a trained external expert. Six months after, each Centre repeated the data collection (POST phase), specular to the PRE. RESULTS: A total of 5200 medical charts were analysed. Pain was documented in 37.5% of the patients. After the educational intervention, the intensity of pain was appropriately assessed in a higher percentage of patients (77.4% vs. 47.8%, p = 0.0001), and it was more frequently monitored during hospitalisation. Qualitative definition of pain (pathogenesis, duration, etc.) increased in POST phase (75.4% vs. 62.7%, p = 0.0001). A 73.3% increase in the use of strong opioids was detected following educational programme. CONCLUSIONS: Pain affects 4 out of 10 patients hospitalised in IM. According to our large real-world study, to implement a standardised one-shot educational programme may persistently improve the attitude of health personnel towards the characterisation and management of pain.

To drain or not to drain extraperitoneal colorectal anastomosis? A systematic review and meta-analysis.

AIM: Anastomotic leakage is the one of the most serious complications in rectal cancer surgery and is associated with high mortality, morbidity and an increased incidence of local recurrence. Although many studies have compared drained and undrained colorectal anastomoses, to date the role of pelvic drainage in extraperitoneal colorectal anastomosis remains undefined. METHOD: We carried out a systematic review of the literature, performing an unrestricted search in MEDLINE and Embase up to 30 October 2012. Reference lists of retrieved articles and review articles were manually searched for other relevant studies. We performed a meta-analysis of the data currently available on the incidence of extraperitoneal anastomotic leakage, according to the presence or absence of pelvic drainage. RESULTS: Overall, eight studies - three randomized clinical trials (RCTs) and five non-RCTs, comprising a total of 2277 patients - were included in the meta-analysis. Pelvic drainage was demonstrated to reduce both the leak rate and the rate of reintervention in patients who underwent anterior rectal resection with extraperitoneal colorectal anastomosis (OR = 0.51, 95% CI: 0.36-0.73; and OR = 0.29, 95% CI: 0.18-0.46, respectively) compared with patients without drainage. Overall mortality and infection rates were also evaluated, but a nonsignificant correlation was found with the presence of drainage. CONCLUSION: The meta-analysis shows that the presence of a pelvic drain reduces the incidence of extraperitoneal colorectal anastomotic leakage and the rate of reintervention after anterior rectal resection.

[Workplace campaigns for metabolic syndrome prevention and healthy lifestyles promotion in mechanical engineering industries]. / Interventi per la prevenzione della sindrome metabolica e la promozione di stili di vita salutari in aziende del settore metalmeccanico.

The paper describes 2 years outcome on BMI, smoking habits and physical activity of 2 WHP carried in engineering plants. Three important results were achieved: stationarity of body weight despite ageing of examined population; increase of workers that perform regular physical activity and a slight increase of smoking cessation. NSAS questionnaire showed a marked improvement in life styles compared to the data obtained 2 years before. Our findings suggest that an efficacy on life style modification can be achieved by WHP campaigns with little time and cost consuming. The collaboration between occupational physician, employer and employees but also with external professionals is the key of success.

Performance of recalibrated ReFacto laboratory standard in the measurement of FVIII plasma concentration via the chromogenic and one-stage assays after infusion of recalibrated ReFacto (B-domain deleted recombinant factor VIII).

The use of ReFacto Laboratory Standard (RLS) in the one-stage clotting assay was proposed to reduce the underestimation of factor VIII (FVIII) plasma concentration after the infusion of 'ReFacto' (B-domain deleted recombinant FVIII) in haemophilia A patients. Both ReFacto and RLS were recently recalibrated, with the resulting materials containing approximately 20% more protein than the previous products. The aim of this study was to evaluate the performance of recalibrated RLS in the measurement of FVIII plasma concentration after the infusion of recalibrated ReFacto. In 13 severe haemophilia A patients, 25 IU kg(-1) of ReFacto were injected intravenously. Venous blood samples were collected at 0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h after the end of the infusion. Pharmacokinetic parameters were measured for the chromogenic and one-stage assays using International Plasma Standard (IPS) and RLS for both assays and assuming a non-compartmental drug disposition. Comparisons among assays and standards were performed using anova. Pharmacokinetic estimates obtained with the chromogenic method were in agreement with those published in the literature. The one-stage method was confirmed to be more sensitive to lower plasma concentrations of FVIII. The measured maximum plasma concentration (C(max)) was slightly higher than theoretical values and independent of the assay used. C(max), area under the curve (AUC) and volume of distribution at steady state (V(ss)) presented non-significant differences among the methods and standards used. The clinical utility of RLS in the evaluation of FVIII concentration after the infusion of ReFacto seems to be reduced since recalibration of the product.

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Deep Vein Thrombosis in Europe-Health-Related Quality of Life and Mortality.

OBJECTIVES: Deep vein thrombosis (DVT) is a major health-care burden in Europe, but exact estimates are lacking. This study reports results from the PREFER venous thromboembolism (VTE) study concerning health-related quality of life (HrQoL) and mortality of patients with DVT. METHODS: PREFER VTE was a prospective, observational study, conducted in 7 European countries, designed to provide data concerning treatment patterns, resource utilization, mortality, and QoL. First-time or recurrent patients with DVT were followed at 1, 3, 6, and 12 months. Health-related QoL-as measured by the EuroQoL 5-Dimension 5-Level instrument ( EQ-5D-5L)-was analyzed using Tobit regression with repeated measures, assessing the impact of baseline characteristics stratified by cancer activity. Mortality was analyzed using logistic regression. RESULTS: At baseline, patients with DVT had a 0.14 lower EQ-5D-5L index score (0.72 for total sample) compared to the reference UK population (0.85). The EQ-5D-5L index score improved from baseline to 12 months in patients with active cancer (from 0.70 to 0.79) and those without (0.72-0.87); 7.3% died within a year, a 5.2% excess mortality compared to the age- and gender-adfjusted general population. The 12-month mortality rate of DVT varied between 2.9% in the pooled data from Germany, Switzerland, or Austria and 15.4% in Italy. Furthermore, the mortality rate differed between patients with active cancer and those without (42.9% vs 4.7%). CONCLUSIONS: Deep vein thrombosis is associated with a substantial burden of illness in terms of HrQoL at baseline, which following treatment normalizes after 12 months and has a significant mortality rate. In addition, active cancer has a significant impact on mortality and the HrQoL of patients with DVT.

Association between inherited thrombophilic abnormalities and central venous catheter thrombosis in patients with cancer: a meta-analysis.

BACKGROUND: The risk of deep vein thrombosis (DVT) is increased in cancer patients with central venous catheters (CVC). Factor (F)V Leiden and the G20210A prothrombin mutation (PTM) may play a role in causing catheter-related DVT in patients with cancer. However, information on the association between these thrombophilic abnormalities and CVC-related thrombosis are scarce. PURPOSE: To assess the risk of CVC-related thrombosis associated with these two thrombophilic disorders. METHODS: MEDLINE and EMBASE databases (up to March 2007); reference lists of retrieved articles. Studies comparing the prevalence of prothrombotic abnormalities in cancer patients with CVC-related thrombosis and in a control group of cancer subjects with CVC without thrombosis. Two reviewers independently selected studies and extracted study characteristics, quality and outcomes. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and pooled. RESULTS: Ten studies involving 1000 patients were included. The pooled OR for CVC-related thrombosis was 4.6 (95% CI: 2.6, 8.1) in patients with FV Leiden. The pooled OR for CVC-related thrombosis was 4.9 (95% CI: 1.7, 14.3) in patients with PTM. The estimated attributable risk of CVC-related thrombosis was 13.1% for FV Leiden and 4.5% for PTM. CONCLUSION: Our meta-analysis suggests that the presence of FV Leiden and PTM is associated with CVC-related thrombosis.

Do Italian vascular centers look for isolated calf deep vein thrombosis? Analysis of isolated calf deep vein thromboses included in the ''Master'' Registry.

AIM: Two diagnostic imaging strategies for suspected deep venous thrombosis (DVT) in symptomatic patients are currently used: a serial compression ultrasound examination of proximal veins, or a single complete ultrasound investigation of proximal and distal veins. These strategies lead to different results since only the latter allows diagnosis of isolated calf DVT (ICDVT). METHODS: We analyzed the approach of Italian centers in looking for ICDVT using the observational MASTER registry which prospectively collected information on patients with acute symptomatic venous thromboembolism. RESULTS: ICDVT was diagnosed in 170 of the 1772 patients with leg DVT (9.6%). The rate of diagnosed ICDVT vs total DVT differed between centers from 0% to 24%. Patients with ICDVT were younger (P<0.0001); diagnosis was more frequently delayed (P<0.0001), temporary risk factors were more frequent, cancer was less frequent (P<0.001), and pulmonary embolism (PE) was more frequent at presentation (P<0.05). More ICDVT patients received LMWH only, not followed by oral anticoagulation (P<0.001). CONCLUSIONS: The diagnostic strategy for suspected leg DVT differs greatly among Italian centers. A relatively high rate of PE was recorded in patients with ICDVT for reasons which are open to debate. Prospective, well designed studies on the clinical risks and the need for diagnosing ICDVT, and the advantages/disadvantages of the two diagnostic procedures are urgently needed.

Variation of renal function over time is associated with major bleeding in patients treated with direct oral anticoagulants for atrial fibrillation.

Essential In patients on treatment with direct anticoagulants (DOACs) variation of renal function is common. The effect of variations of renal function over time on major bleeding is not well defined. Variation of renal function over time is an independent predictor of major bleeding. Identifying conditions associated with variation of renal function may increase safety of DOACs. SUMMARY: Background Chronic kidney disease is a risk factor for major bleeding in patients with atrial fibrillation (AF) treated with warfarin. Objective To assess the effect of variations in renal function over time on the risk of major bleeding during treatment with direct oral anticoagulants (DOACs) in patients with non-valvular AF. Methods Consecutive AF patients were prospectively followed after they had received the first DOAC prescription. Estimated glomerular filtration rate (eGFR) was periodically assessed, and the incidence of major bleeding was recorded. A joint survival model was used to estimate the association between variation in eGFR and the risk of major bleeding. Results During a mean follow-up of 575 days, 44 major bleeds occurred in 449 patients (6.1% per patient-year). eGFR over time was inversely and independently associated with the risk of major bleeding; every 1 mL min-1 absolute decrease in eGFR was associated with a 2% increase in the risk of major bleeding (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01-1.04). A similar effect of the variation in eGFR over time was observed on the risk of clinically relevant non-major bleeding (HR 1.02, 95% CI 1.01-1.03). Deterioration of renal function leading to a change in eGFR staging was associated with an increase in the risk of major bleeding (HR 2.43, 95% CI 1.33-4.45). Conclusions Variation in renal function over time is associated with the risk of major bleeding in AF patients treated with DOACs in real life. Identification of intervening clinical conditions associated with variation in renal function is essential to reduce the risk of major bleeding and to make DOAC treatment more safe.

Deep-vein thrombosis in Europe - Burden of illness in relationship to healthcare resource utilization and return to work.

OBJECTIVES: Deep-vein thrombosis (DVT) forms a major healthcare burden in Europe, but exact estimates concerning the economic burden on society are lacking. This study reports results from the PREFER in VTE study concerning resource utilization and absence from work in DVT patients. METHODS: The PREFER in VTE registry was a prospective, observational, multicenter study carried out in Europe (France, Italy, Spain, the UK, and DACH [Germany, Switzerland and Austria]), designed to provide data concerning treatment patterns, resource utilization, mortality and quality of life. Patients with a first-time and/or recurrent DVT, were recruited and followed for 12 months. Data about resource utilization concerns resource utilization related to DVT. Specifically, treatment pattern, re-hospitalization rate, length of hospital stay, ambulatory/office visit, and proportion of patients returning to work, were analyzed and presented. Subgroup analysis by country and active cancer were also conducted. The length of hospital stay was analyzed as a function of demographics, previous events and co-morbidities using zero-inflated binomial negative regression. Similarly, time until return to work was analyzed using Cox regression. RESULTS: A total of 2056 patients with DVT were recruited, with an average age of 60 years. Patients with active cancer were mostly treated with heparin (83.9%), while patients without active cancer were treated with combinations of heparin, VKA and DOACs. DOACs were less often used in Spain and Italy (<7.0%). Following the management of their initial DVT 20.5% of the patients with and 12.2% of patients without active cancer (n = 88; n = 1462) were hospitalized for on average 8.2 and 10.1 days, respectively. The hospitalization-rate was highest in Italy (16.7%) and lowest in France (7.7%). Furthermore, the average length of stay was highest in Italy (16.6 days) and lowest in DACH (5.2 days). Physician visits were highest in DACH (9.3), lowest in the UK (2.6). Of those working, 50% returned to work at 1 month; >30% did not return to work within the year. CONCLUSIONS: Medical treatment of DVT differed between patients with active cancer and those without. Post-VTE or VTE-related resource utilization differs remarkably between countries. Work-loss seems high, but questions may be raised concerning the causality due to the presence of co-morbidities.

Oxygen saturation or respiratory rate to improve risk stratification in hemodynamically stable patients with acute pulmonary embolism.

Essentials In acute pulmonary embolism (PE), risk stratification is essential to drive clinical management. Improving the 2014-ESC risk stratification strategy is crucial in hemodynamically stable patients. Oxygen saturation and respiratory rate improve risk stratification in hemodynamically stable PE. Simple and routine tests improve risk stratification of hemodynamically stable PE. SUMMARY: Background In patients with acute pulmonary embolism (PE), risk stratification for short-term death is recommended to drive clinical management. A risk stratification strategy combining the simplified Pulmonary Embolism Severity Index (PESI), echocardiography and troponin was proposed by the European Society of Cardiology (ESC) in 2014. The identification of hemodynamically stable patients at increased risk of death by this strategy needs improvement. Objective To assess whether further stratification by serial cut-off values of oxygen saturation or respiratory rate improves the accuracy of the ESC risk stratification strategy in hemodynamically stable PE patients. Methods Prospective cohorts of hemodynamically stable patients with PE were merged in a collaborative database. The accuracy of risk stratification for 30-day mortality by the original and a modified 2014 ESC strategy was assessed. Results Overall, 255 patients (27%) were categorized as low, 510 (54%) as intermediate-low and 181 (19%) as intermediate-high risk according to the original 2014 ESC strategy. Thirty-day mortality was 1.2% in low, 10% in intermediate-low and 11% in intermediate-high-risk patients. By adding oxygen saturation in air of < 88%, the discriminatory power of the 2014 ESC model improved for 30-day mortality (c-statistics, 0.71; 95% confidence interval [CI], 0.65-0.77 vs. 0.63, 95% CI, 0.56-0.69) and for PE-related death (c-statistics, 0.75; 95% CI, 0.69-0.81 vs. 0.63, 95% CI 0.56-0.69). Conclusions Simple and routine tests, such as oxygen saturation or respiratory rate, could be added to the 2014 ESC strategy for risk stratification to identify hemodynamically stable PE patients at increased risk of death who are potentially candidates for more aggressive treatment.

State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.

A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement.

BACKGROUND: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. OBJECTIVES: The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin. METHODS: In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint. RESULTS: Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients. CONCLUSIONS: Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.

A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery.

BACKGROUND: YM150, a new oral direct factor Xa inhibitor is used as prophylaxis for venous thromboembolism (VTE), a well-known risk after orthopaedic surgery. OBJECTIVES: To assess the safety and efficacy of thromboprophylaxis with YM150 in a dose escalation study. PATIENTS/METHODS: Patients (174) undergoing hip replacement surgery were randomized per cohort to oral once daily YM150 or subcutaneous enoxaparin (40 mg daily) in a 4:1 ratio for 7-10 days treatment. The YM150 doses were 3, 10, 30 and 60 mg by sequential four-dose escalation cohorts. The primary endpoint was major and/or clinically relevant non-major bleeding. The incidence of VTE was defined as a composite of verified symptomatic events and/or positive findings at bilateral venography on the last treatment day. An independent adjudication committee evaluated blindly the outcomes of the open-label study. RESULTS: No major and three clinically relevant non-major bleeds were reported, 1 (2.9%; 95% CI, 0.1-15.1) in the 3 mg and 2 (5.7%; 95% CI, 1.0-18.8) in the 10 mg YM150 dose groups. Of 147 patients (84%) with an evaluable venogram, VTE was observed in 51.9% (95% CI, 31.9-71.4), 38.7% (95% CI, 22.6-57.0), 22.6% (95% CI, 9.7-39.4), and 18.5% (95% CI, 7.5-36.5) in the YM150 dose groups 3, 10, 30 and 60 mg, respectively. A significant YM150 dose-related trend in VTE incidence was found (P=0.006). VTE with enoxaparin was 38.7% (95% CI, 22.6-57.0). CONCLUSIONS: YM150, 10-60 mg daily, starting 6-10 h after primary hip replacement, was shown to be safe, well tolerated and effective.