Impact of electronic cigarettes (e-cigs) and heat-not-burn/heated tobacco products (HnB/HTP) on asthma and chronic obstructive pulmonary disease: a viewpoint of the Italian Society of Internal Medicine.

The association of cigarette smoking with several severe and very severe diseases (oncological, cardiovascular, respiratory) which have dramatic epidemiological, medical, and financial impact, is a well-known public threat. Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent diseases in Italy, posing significant public health challenges. Tobacco smoking, a primary risk factor for COPD and a common asthma trigger, remains a critical preventable public health issue. While universally acknowledged that quitting smoking drastically reduces the risk of smoking-related health issues, a significant portion of smokers and patients find quitting challenging or undesirable, hence a need for new ways to deal with it. A worth considering alternative might be the switch to electronic cigarettes (e-cig), and heat-not-burn/heated tobacco products (HnB/HTP). Emerging evidence suggests potential benefits in asthma and COPD management when transitioning from traditional smoking to e-cigs or HnB devices. However, the effectiveness of these products in facilitating smoking cessation is still debated, alongside concerns about their role in promoting smoking initiation among non-smokers. Internists are among the physicians who most frequently assist patients with smoking-related diseases, and in this perspective they cannot avoid paying attention to the progressive diffusion of smoking products alternative to the traditional cigarette, and to the controversies with respect to their use. In this context, the Italian Society of Internal Medicine, also recognizing a growing need for clarity for healthcare providers, has undertaken a comprehensive analysis of existing literature to offer an informed perspective on the health impact of e-cigs and HnB/HTP on asthma and COPD.

Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer.

The clinical benefit of extended prophylaxis for venous thromboembolism (VTE) after laparoscopic surgery for cancer is unclear. The efficacy and safety of direct oral anticoagulants for this indication are unexplored. PROphylaxis of venous thromboembolism after LAParoscopic Surgery for colorectal cancer Study II (PROLAPS II) was a randomized, double-blind, placebo-controlled, investigator-initiated, superiority study aimed at assessing the efficacy and safety of extended prophylaxis with rivaroxaban after laparoscopic surgery for colorectal cancer. Consecutive patients who had laparoscopic surgery for colorectal cancer were randomized to receive rivaroxaban (10 mg once daily) or a placebo to be started at 7 ± 2 days after surgery and given for the subsequent 3 weeks. All patients received antithrombotic prophylaxis with low-molecular-weight heparin from surgery to randomization. The primary study outcome was the composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected deep vein thrombosis (DVT), or VTE-related death at 28 ± 2 days after surgery. The primary safety outcome was major bleeding. Patient recruitment was prematurely closed due to study drug expiry after the inclusion of 582 of the 646 planned patients. A primary study outcome event occurred in 11 of 282 patients in the placebo group compared with 3 of 287 in the rivaroxaban group (3.9 vs 1.0%; odds ratio, 0.26; 95% confidence interval [CI], 0.07-0.94; log-rank P = .032). Major bleeding occurred in none of the patients in the placebo group and 2 patients in the rivaroxaban group (incidence rate 0.7%; 95% CI, 0-1.0). Oral rivaroxaban was more effective than placebo for extended prevention of VTE after laparoscopic surgery for colorectal cancer without an increase in major bleeding. This trial was registered at www.clinicaltrials.gov as #NCT03055026.

Recurrent venous thromboembolism and major bleeding in patients with localised, locally advanced or metastatic cancer: an analysis of the Caravaggio study.

BACKGROUND: Patients with cancer-associated venous thromboembolism (VTE) have a high risk of VTE recurrence and anticoagulant treatment-related bleeding, but the correlation of these risks with the cancer stage is unclear. METHODS: We evaluated the risks of VTE recurrence and treatment-related major bleeding according to the cancer stage in patients with VTE and solid cancer randomised to apixaban or dalteparin in the Caravaggio study. Cancer stage was categorised by expert cancer physicians according to pre-specified criteria, and study outcomes were adjudicated by an independent committee unaware of cancer stage and treatment allocation. RESULTS: Of the 1034 patients included in this analysis, 217 (21.0%) had localised cancer, 279 (27.0%) locally advanced cancer and 503 (48.7%) metastatic cancer. Cancer stage was undetermined in 35 patients (3.4%). VTE recurrence and major bleeding rates were 2.8% and 3.2% in patients with localised cancer, respectively. In comparison to patients with localised cancer, the VTE recurrence rate was higher in patients with locally advanced cancer (7.5%, hazard ratio [HR] = 2.8, 95% confidence interval [CI] = 1.1-6.9) and metastatic cancer (8.7%, HR = 3.3, CI = 1.4-7.7, CI). Patients with metastatic cancer had numerically increased major bleedings compared to those with localised cancer (5.2%, HR = 1.65, CI = 0.7-3.8). The efficacy and safety of apixaban and dalteparin across patients with different cancer stages were consistent with the findings observed in the overall patients with cancer randomised in the study. CONCLUSIONS: Patients with locally advanced and metastatic cancer have a higher rate of VTE recurrence than patients with localised cancer with no statistically significant difference in treatment-related major bleeding.

Apixaban and Dalteparin for the Treatment of Venous Thromboembolism in Patients with Different Sites of Cancer.

Efficacy and safety of anticoagulant treatment for venous thromboembolism (VTE) may vary in patients with different cancer sites. We evaluated the rates of VTE recurrence and major bleeding and the relative efficacy and safety of 6-month treatment with oral apixaban or subcutaneous dalteparin in patients with different cancer sites randomized in the Caravaggio study. Primary cancer was located at gastrointestinal sites in 375 patients (32.5%), lung in 200 (17.3%), breast in 155 (13.4%), genitourinary sites in 139 (12%), gynecological sites in 119 (10.3%), and was hematological in 85 patients (7.4%). Rates of VTE recurrence were 10.9% in patients with gynecological, 8.8% with gastrointestinal, 6.5% with genitourinary, and 5.5% with lung cancer with lower rates in the other sites of cancer. Rates of major bleeding were 7.2% in patients with genitourinary and 4.8% with gastrointestinal cancer, with lower rates in patients with other sites of cancer. The observed absolute risk difference in VTE recurrence in favor of apixaban was 11.9% in patients with gynecological, 5.5% with lung, 3.7% with genitourinary cancer, and 0.6% with gastrointestinal cancer. None of the risk differences was statistically significant. The rates of major bleeding in patients treated with apixaban or dalteparin was similar across patients with different cancer sites. In conclusion, recurrences appear to be more common in patients with gastrointestinal and gynecological cancer and major bleedings in patients with genitourinary and gastrointestinal cancer. Oral apixaban is a valid oral alternative to subcutaneous dalteparin for the treatment of a large spectrum of patients with cancer-associated VTE.

Health outcomes in COPD smokers using heated tobacco products: a 3-year follow-up.

Given that many patients with chronic obstructive pulmonary disease (COPD) smoke despite their symptoms, it is important to understand the long-term health impact of cigarette substitution with heated tobacco products (HTPs). We monitored health parameters for 3 years in COPD patients who substantially attenuated or ceased cigarette consumption after switching to HTPs. Changes in daily cigarette smoking, annualized disease exacerbations, lung function indices, patient-reported outcomes (CAT scores) and 6-minute walk distance (6MWD) from baseline were measured in COPD patients using HTPs at 12, 24 and 36 months. These were compared to a group of age- and sex-matched COPD patients who continued smoking. Complete data sets were available for 38 patients (19 in each group). Subjects using HTPs had a substantial decrease in annualized COPD exacerbations within the group mean (± SD) from 2.1 (± 0.9) at baseline to 1.4 (± 0.8), 1.2 (± 0.8) and 1.3 (± 0.8) at 12-, 24- and 36-month follow-up (p < 0.05 for all visits). In addition, substantial and clinically significant improvements in CAT scores and 6MWD were identified at all three time points in the HTP cohort. No significant changes were observed in COPD patients who continued smoking. This study is the first to describe the long-term health effects of HTP use in COPD patients. Consistent improvements in respiratory symptoms, exercise tolerance, quality of life, and rate of disease exacerbations were observed in patients with COPD who abstained from smoking or substantially reduced their cigarette consumption by switching to HTP use.

Bleeding with Apixaban and Dalteparin in Patients with Cancer-Associated Venous Thromboembolism: Results from the Caravaggio Study.

BACKGROUND: Direct oral anticoagulants are recommended for the treatment of cancer-associated thrombosis (CAT) as an alternative to low-molecular-weight heparin (LMWH), but an increased bleeding risk in patients with gastrointestinal cancer was reported. The Caravaggio study compared apixaban and dalteparin for the treatment of patients with CAT. Here we describe sites of bleeding, associated cancer sites, clinical presentation, and course of major bleeding in patients included in the Caravaggio study. METHODS: The Caravaggio study was a multinational, randomized, open-label, noninferiority study. Bleeding events and the severity of major bleedings were adjudicated by a committee unaware of treatment allocation using predefined criteria; for the purpose of this analysis, data were analyzed in the safety population. RESULTS: Major bleeding occurred in 22 of 576 patients on apixaban (3.8%) and in 23 of 579 patients on dalteparin (4.0%). The sites of major bleeding and their distribution according to the type of cancer were similar between the two treatment groups. Major bleeding occurred in nine patients with gastrointestinal cancer in each treatment group. The clinical presentation of major bleeding was severe or fatal in 6 patients on apixaban and in 5 patients on dalteparin, while the clinical course was severe in 5 patients on apixaban and in 7 patients on dalteparin. CONCLUSION: Apixaban is a safe alternative to LMWH for the treatment in patients with CAT. No excess in gastrointestinal bleeding was observed in patients who received apixaban, including those with gastrointestinal cancer.

Lessons learned from COVID-19 for clinical research operations in Italy: what have we learned and what can we apply in the future?

The coronavirus disease 2019 (COVID-19) pandemic has stressed the importance of health research as never before. In the specific domain of clinical research, the effort to rapidly find responses to health challenges and therapeutic hypotheses has highlighted the need for efficient, timely, ethically correct research. The guidelines published by the Agenzia Italiana del Farmaco have shown that some useful changes are feasible: simple and rapid methods have been implemented to conduct clinical research in the emergency conditions of the pandemic, maintaining high levels of quality. In this perspective, four Italian scientific associations operating in clinical research have worked together to evaluate which measures, among the ones implemented during the pandemic, have been particularly significant and potentially effective under normal conditions or in case of emergencies, and that therefore will be useful in the future as well.

Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer.

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use. METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding. RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P<0.001 for noninferiority). Major bleeding occurred in 22 patients (3.8%) in the apixaban group and in 23 patients (4.0%) in the dalteparin group (hazard ratio, 0.82; 95% CI, 0.40 to 1.69; P = 0.60). CONCLUSIONS: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding. (Funded by the Bristol-Myers Squibb-Pfizer Alliance; Caravaggio ClinicalTrials.gov number, NCT03045406.).

Acquired Factor XIII Deficiency Inducing Recurrent and Fatal Bleeding, Description of a Case.

Factor XIII deficiency may be inherited or acquired. Inherited deficiency is associated with signs and symptoms of minor bleeding from a young age, and possible major bleeding complications, in particular during pregnancy. On the other hand, acquired factor XIII deficiency is usually associated with severe symptoms of major bleeding, in particular during surgery. In this paper, we report an interesting case of recurrent major bleeding with subsequent fatal bleeding in an adult man diagnosed with acquired factor XIII deficiency.

Rivaroxaban for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer. Design of the PRO-LAPS II STUDY.

BACKGROUND: The clinical benefit of extending prophylaxis for venous thromboembolism (VTE) beyond hospital discharge after laparoscopic surgery for cancer is undefined. Extended prophylaxis with rivaroxaban is effective in reducing post-operative VTE after major orthopedic surgery without safety concern. METHODS: PROLAPS II is an investigator-initiated, randomized, double-blind study aimed at assessing the efficacy and safety of extended antithrombotic prophylaxis with rivaroxaban compared with placebo after laparoscopic surgery for colorectal cancer in patients who had received antithrombotic prophylaxis with low molecular-weight heparin for 7 ± 2 days (NCT03055026). Patients are randomized to receive rivaroxaban (10 mg once daily) or placebo for 3 weeks (up to day 28 ± 2 from surgery). The primary study outcome is a composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected DVT or VTE-related death at 28 ± 2 days from laparoscopic surgery. The primary safety outcome is major bleeding defined according to the International Society of Thrombosis and Haemostasis. Symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected DVT, major bleeding or death by day 28 ± 2 and by day 90 from surgery are secondary outcomes. Assuming an 8% event rate with placebo and 60% reduction in the primary study outcome with rivaroxaban, 323 patients per group are necessary to show a statistically significant difference between the study groups. DISCUSSION: The PROLAPS II is the first study with an oral anti-Xa agent in cancer surgery. The study has the potential to improve clinical practice by answering the question on the clinical benefit of extending prophylaxis after laparoscopic surgery for colorectal cancer.

Prophylaxis of Venous Thromboembolism after Hospital Discharge in Internal Medicine: Findings from the Observational FADOI-NoTEVole Study.

BACKGROUND AND AIM: Post-discharge prophylaxis for venous thromboembolism (VTE) is a challenging issue in patients hospitalised in Internal Medicine Units (IMUs). The aim of this study was to evaluate the frequency and the factors associated with post-discharge prophylaxis for VTE in IMUs. METHODS: Multi-centre, retrospective study including consecutive patients who were admitted for any cause and discharged from an IMU. RESULTS: Overall, 3,740 patients (mean age 74.1 ± 15.7 years) were included in the study at 38 IMUs in Italy. At discharge, the percentage of patients receiving pharmacological thromboprophylaxis was 16.0% (20.1% after excluding patients treated with anticoagulants for indications other than VTE prophylaxis). At multivariable analysis, history of ischaemic stroke, hypomobility ≥ 7 days, central venous catheter, ≥ 10 versus ≤ 5 days of hospital stay, use of corticosteroids, cancer, history of falls, availability of a caregiver, infections and age were significantly associated with thromboprophylaxis, while an inverse correlation was observed with concomitant anti-platelet drugs and platelet count < 70,000/mm3. Patients with a Padua Prediction Score ≥ 4 versus < 4 and with an IMPROVE bleeding score ≥ 7 versus < 7 more frequently received prophylaxis at discharge (31.2% vs. 10.6%, p < 0.0001, and 25.7% vs. 19.6%, p = 0.028, respectively). CONCLUSION: In this study, one in five patients discharged from an Italian IMU received prophylaxis for VTE. The perceived thrombotic risk is significantly related to the use of prophylaxis.

Apixaban versus Dalteparin for the Treatment of Acute Venous Thromboembolism in Patients with Cancer: The Caravaggio Study.

International and national guidelines recommend low-molecular-weight heparin for the treatment of venous thromboembolism (VTE) in patients with cancer. The aim of the Caravaggio study is to assess whether oral apixaban is non-inferior to subcutaneous dalteparin for the treatment of acute proximal deep vein thrombosis and/or pulmonary embolism in patients with cancer. The study is an investigator-initiated, multi-national, prospective, randomized, open-label with blind end-point evaluation (PROBE), non-inferiority clinical trial (NCT03045406). Consecutive patients are randomized to receive oral apixaban or subcutaneous dalteparin for 6 months. Apixaban is given at a dose of 10 mg twice daily for the first 7 days and then 5 mg twice daily; dalteparin is given at a dose of 200 IU/kg for the first month and then 150 IU/kg once daily. The primary outcome of the study is objectively confirmed recurrent VTE as assessed by a central independent adjudication committee unaware of study treatment allocation. The primary safety outcome is major bleeding defined according to the guidelines of the International Society of Thrombosis and Haemostasis. Assuming a 6-month incidence of the primary outcome of 7% with dalteparin and an upper limit of the two-sided 95% confidence interval of the hazard ratio below the pre-specified margin of 2.00, 1,168 patients will be randomized considering an up to 20% loss in total patient-years (ß = 80%; α one-sided = 0.025). The Caravaggio study has the potential, along with other recently performed or on-going studies, to make less cumbersome the management of VTE in patients with cancer by replacing parenteral with oral anticoagulation.

Epidemiology and outcome of Clostridium difficile infections in patients hospitalized in Internal Medicine: findings from the nationwide FADOI-PRACTICE study.

BACKGROUND: Clostridium difficile (CD) is a leading cause of diarrhoea among hospitalized patients. The objective of this study was to evaluate the rate, the optimal diagnostic work-up, and outcome of CD infections (CDI) in Internal Medicine (IM) wards in Italy. METHODS: PRACTICE is an observational prospective study, involving 40 IM Units and evaluating all consecutive patients hospitalized during a 4-month period. CDI were defined in case of diarrhoea when both enzyme immunoassay for GDH, and test for A/B toxin were positive. Patients with CDI were followed-up for recurrences for 4 weeks after the end of therapy. RESULTS: Among the 10,780 patients observed, 103 (0.96 %) showed CDI, at admission or during hospitalization. A positive history for CD, antibiotics in the previous 4 weeks, recent hospitalization, female gender and age were significantly associated with CDI (multivariable analysis). In-hospital mortality was 16.5 % in CD group vs 6.7 % in No-CD group (p < 0.001), whereas median length of hospital stay was 16 (IQR = 13) vs 8 (IQR = 8) days (p < 0.001) among patients with or without CDI, respectively. Rate of CD recurrences was 14.6 %. As a post-hoc evaluation, 23 out of 34 GDH+/Tox- samples were toxin positive, when analysed by molecular method (a real-time PCR assay). The overall CD incidence rate was 5.3/10,000 patient-days. CONCLUSIONS: Our results confirm the severity of CDI in medical wards, showing high in-hospital mortality, prolonged hospitalization and frequent short-term recurrences. Further, our survey supports a 2-3 step algorithm for CD diagnosis: EIA for detecting GDH, A and B toxin, followed by a molecular method in case of toxin-negative samples.

Influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism.

BACKGROUND: The influence of recent immobilization or surgery on mortality in cancer patients with venous thromboembolism (VTE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to compare the 3-month mortality rate in cancer patients with VTE, with patients categorized according to the presence of recent immobilization, surgery or neither. The major outcomes were fatal pulmonary embolism (PE) and fatal bleeding within the first 3 months. RESULTS: Of 6,746 patients with active cancer and acute VTE, 1,224 (18%) had recent immobilization, 1,055 (16%) recent surgery, and 4,467 (66%) had neither. The all-cause mortality was 23.4% (95% CI: 22.4-24.5), and the PE-related mortality: 2.5% (95% CI: 2.1-2.9). Four in every ten patients dying of PE had recent immobilization (37%) or surgery (5.4%). Only 28% of patients with immobilization had received prophylaxis, as compared with 67% of the surgical. Fatal PE was more common in patients with recent immobilization (5.0%; 95% CI: 3.9-6.3) than in those with surgery (0.8%; 95% CI: 0.4-1.6) or neither (2.2%; 95% CI: 1.8-2.6). On multivariate analysis, patients with immobilization were at an increased risk for fatal PE (odds ratio: 1.8; 95% CI: 1.2-2.5). CONCLUSIONS: One in every three cancer patients dying of PE had recent immobilization for ≥ 4 days. Many of these deaths could have been prevented with adequate thromboprophylaxis.

Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry.

Patients with venous thromboembolism (VTE), and particularly those with cancer, are at increased risk of recurrences, major bleeding, and short- / medium-term mortality. Data from 35,539 patients (6,075 of these with cancer), presenting with symptomatic VTE in the previous three months and enrolled in the worldwide RIETE registry, were evaluated to assess overall and pulmonary embolism (PE)-related mortality, and their potential predictors, with particular focus on patients with cancer. Overall 3-month mortality in the total RIETE population was 7.9%, and death was considered PE-related in 1.4%. Significantly more patients died among those with cancer (26.4%, vs 4.1% in no-cancer group, p<0.001). In 3.0% of cancer patients death was considered PE-related, compared to 1.0% in no-cancer group (p<0.001). Cancer was the strongest independent risk factor for both all-cause and PE-related mortality, and in the subgroup of cancer patients those with advanced disease, reduced mobility, chronic pulmonary disease, and those experiencing PE (vs isolated deep vein thrombosis) were at increased risk of PE-related death. According to the findings of our very large, real-world registry, in the three months following an acute episode VTE remains a substantial cause of mortality. Cancer patients are at particular high risk of VTE-related death. Clinical factors predicting a fatal PE identified in this study (cancer, immobility, comorbidities, increasing age, PE at presentation), could be considered for risk stratification scheme for secondary prophylaxis in daily practice.

Incidence and predictors of venous thromboembolism in post-acute care patients. A prospective cohort study.

Few studies have addressed the topic of venous thromboembolism (VTE) in patients hospitalised in rehabilitation facilities. This patient population is rapidly growing, and data aimed to better define VTE risk in this setting are needed. Primary aim of this prospective observational study was to evaluate the frequency of symptomatic, objectively confirmed VTE in a cohort of unselected consecutive patients admitted to rehabilitation facilities, after medical diseases or surgery. Further objectives were to assess overall mortality, to identify risk factors for VTE and mortality, and to assess the attitude of physicians towards thromboprophylaxis. A total of 3,039 patients were included in the study, and the median duration of hospitalisation was 26 days. Seventy-two patients (2.4%) had symptomatic VTE. The median time to VTE from admission to the long-term care unit was 13 days. According to multivariable analysis, previous VTE (hazard ratio 5.67, 95% confidence interval 3.30-9.77) and cancer (hazard ratio 2.26, 95% confidence interval 1.36-3.75) were significantly associated to the occurrence of VTE. Overall in-hospital mortality was 15.1%. Age over 75 years, male gender, disability, cancer, and the absence of thromboprophylaxis were significantly associated to an increased risk of death (multivariable analysis). In-hospital antithrombotic prophylaxis was administered to 75.1% of patients, and low-molecular-weight heparin was the most widely used agent. According to our study, patients admitted to rehabilitation facilities remain at substantially increased risk for VTE. Because this applies to the majority of these patients, there is a great need for clinical trials assessing optimal prophylactic strategies.

Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study.

BACKGROUND: Clinical trials are needed to assess the clinical benefit of antithrombotic prophylaxis in patients with cancer who are receiving chemotherapy, since these patients are at an increased risk of developing a thromboembolism. We did a trial to assess the clinical benefit of the low-molecular-weight heparin nadroparin for the prophylaxis of thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancer. METHODS: Between October, 2003, and May, 2007, ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer were randomly assigned in a double-blind manner to receive subcutaneous injections of nadroparin (3800 IU anti-Xa once a day, n=779) or placebo (n=387), in a 2:1 ratio. Study treatment was given for the duration of chemotherapy up to a maximum of 4 months. The primary study outcome was the composite of symptomatic venous or arterial thromboembolic events, as assessed by an independent adjudication committee. All randomised patients who received at least one dose of study treatment were included in the efficacy and safety analyses (modified intention-to-treat population). The study is registered with ClinicalTrials.gov, NCT 00951574. FINDINGS: 1150 patients were included in the primary efficacy and safety analyses: 769 patients in the nadroparin group and 381 patients in the placebo group. 15 (2.0%) of 769 patients treated with nadroparin and 15 (3.9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p=0.02). Five (0.7%) of 769 patients in the nadroparin group and no patients in the placebo group had a major bleeding event (two-sided p=0.18). The incidences of minor bleeding were 7.4% (57 of 769) with nadroparin and 7.9% (30 of 381) with placebo. There were 121 (15.7%) serious adverse events in the nadroparin goup and 67 (17.6%) serious adverse events in the placebo group. INTERPRETATION: Nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy. Future studies should focus on patients who are at a high risk for thromboembolic events. FUNDING: Italfarmaco SpA, Milan, Italy.

Clinically overt venous thromboembolism after urologic cancer surgery: results from the @RISTOS Study.

OBJECTIVE: Incidence of venous thromboembolism (VTE) and need for thromboprophylaxis in urologic surgery have received little attention since only one randomised study has addressed this issue in the last 20 yr. The present prospective observational study evaluated incidence and risk factors for clinically overt VTE in a wide spectrum of consecutive patients undergoing surgery for cancer and compared findings in urologic patients with those in patients undergoing general or gynaecologic surgery. METHODS: Patients having cancer surgery (general surgery, gynaecology, urology) were assessed for clinically overt VTE occurring up to 30+/-5 d after intervention or more if the hospital stay was longer. All suspected VTE events were evaluated by an external independent Adjudication Committee. RESULTS: A total of 2373 patients, 1238 (52%) undergoing general surgery, 685 (29%) urologic, and 450 (19%) gynaecologic surgery were evaluated. In urologic patients, most procedures (61%) were endoscopic, with bladder and prostate cancer being the most frequent tumours. In-hospital thromboprophylaxis was given to 71.7% of patients, whereas 32.5% received prophylaxis after discharge. The incidence of VTE in urologic patients was lower (0.87%) than that in general surgery and gynaecologic patients (2.8% and 2.0%, respectively). VTE consisted of three cases of nonfatal and three cases of fatal pulmonary embolism (PE). In four of the six cases, VTE occurred during prophylaxis. CONCLUSIONS: VTE still represents a severe complication and remains the most common cause of death after urologic cancer surgery. Efforts should be made to optimise prophylactic measures to further reduce such risk.