Exercise Therapy for Chronic Symptomatic Peripheral Artery Disease: A Clinical Consensus Document of the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases in Collaboration With the European Society of Vascular Medicine and the European Society for Vascular Surgery.

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.

Venous thromboembolism secondary to hospitalization for COVID-19: patient management and long-term outcomes.

Background: Venous thromboembolism (VTE) is a complication of COVID-19 in hospitalized patients. Little information is available on long-term outcomes of VTE in this population. Objectives: We aimed to compare the characteristics, management strategies, and long-term clinical outcomes between patients with COVID-19-associated VTE and patients with VTE provoked by hospitalization for other acute medical illnesses. Methods: This is an observational cohort study, with a prospective cohort of 278 patients with COVID-19-associated VTE enrolled between 2020 and 2021 and a comparison cohort of 300 patients without COVID-19 enrolled in the ongoing START2-Register between 2018 and 2020. Exclusion criteria included age <18 years, other indications to anticoagulant treatment, active cancer, recent (<3 months) major surgery, trauma, pregnancy, and participation in interventional studies. All patients were followed up for a minimum of 12 months after treatment discontinuation. Primary end point was the occurrence of venous and arterial thrombotic events. Results: Patients with VTE secondary to COVID-19 had more frequent pulmonary embolism without deep vein thrombosis than controls (83.1% vs 46.2%, P <.001), lower prevalence of chronic inflammatory disease (1.4% and 16.3%, P <.001), and history of VTE (5.0% and 19.0%, P <.001). The median duration of anticoagulant treatment (194 and 225 days, P = 0.9) and the proportion of patients who discontinued anticoagulation (78.0% and 75.0%, P = 0.4) were similar between the 2 groups. Thrombotic event rates after discontinuation were 1.5 and 2.6 per 100 patient-years, respectively (P = 0.4). Conclusion: The risk of recurrent thrombotic events in patients with COVID-19-associated VTE is low and similar to the risk observed in patients with VTE secondary to hospitalization for other medical diseases.

Multidisciplinary Care for the Prevention and Treatment of Venous Thromboembolism in Patients with Cancer-Associated Thrombosis (CAT): Impact of Educational Interventions on CAT-Related Events and on Patients' and Clinicians' Awareness.

Cancer is a leading cause of death. Venous thromboembolism (VTE) is an often-overlooked cause of morbidity and mortality in cancer patients that can be readily prevented and treated. Actions are needed to reduce the morbidity and mortality of patients with cancer-associated thrombosis (CAT). There is a need to increase awareness of the impact of CAT on cancer patients' morbidity and mortality, on their quality of life and to understand the importance of more effective preventions and treatments of VTE in cancer patients. Moreover, it is of great importance to systematically assess the risk of VTE in regard to patients, cancer and treatment-related factors. Unfortunately, there are unmet clinical needs in the prevention and treatment of cancer-associated VTE. In this review, we discuss an action plan to ensure an increased awareness of and education on the issues that need to be addressed in order to improve the provision of appropriate prevention, early diagnosis and effective and safe treatment of VTE to all cancer patients and, ultimately, to reduce morbidity and mortality.

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.

The European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)-clinical phenotypes and their predictors based on a cohort of 1000 patients.

AIMS: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections. METHODS AND RESULTS: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on computed tomography angiography, magnetic resonance angiography, and/or catheter-based angiography were eligible. Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46 ± 16 years (12% ≥65 years old), 86% were hypertensive, 72% had multifocal, and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65 years old had more often multifocal FMD, lower estimated glomerular filtration rate and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection, and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke, and multivessel FMD. CONCLUSIONS: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management, and follow-up of FMD.

Outcomes after venous thromboembolism in patients with gastric cancer: Analysis of the RIETE Registry.

Gastric cancer is the fifth most common malignancy worldwide. Venous thromboembolism is an independent predictor of death among patients with gastric cancer. We aimed to describe the factors associated with mortality, thrombosis recurrence, and bleeding complications in patients with gastric cancer who develop venous thromboembolism. We included 612 patients with gastric cancer and venous thromboembolism in the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry from 2001 to 2018. We used Cox proportional hazard ratios and a Fine-Gray model to define factors associated with outcomes. The overall mortality at 6 months was 44.4%. Factors associated with increased 6-month mortality included immobility (HR 1.8, 95% CI 1.3-2.4; p < 0.001), anemia (HR 1.4, 95% CI 1.1-1.8; p < 0.02), and leukocytosis (HR 1.8, 95% CI 1.4-2.3; p < 0.001). Recurrent thrombosis occurred in 6.5% of patients and major bleeding complications in 8.5% of the cohort. Male sex was the main factor associated with thrombosis recurrence (HR 2.1, 95% CI 1.1-4.0; p < 0.02) and hemoglobin below 10 g/dL (HR 1.6, 95% CI 1.05-2.50; p = 0.03) the main factor associated with bleeding. In conclusion, patients with gastric cancer who develop venous thrombosis have a very high likelihood of death. Low hemoglobin in this population is associated with poor outcomes.

Upper extremity deep vein thrombosis treated with direct oral anticoagulants: a multi-center real world experience.

Upper-extremity deep vein thrombosis (UEDVT) accounts for about 5-10% of all cases of deep vein thrombosis (DVT). It is often associated with cancer and/or presence of a central venous catheter (CVC), but it may also occur in the absence of these favoring conditions. The safety and efficacy of using direct oral anticoagulants (DOACs) in subjects with UEDVT has not been systematically evaluated and the only data available in the literature derive from anecdotal evidence, analysis of registries, and small single-centre studies. In addition, a specific analysis of UEDVT not associated with cancer and/or CVC has never been made. In this study, we specifically focused on patients with no cancer and without a CVC who were diagnosed with a first episode of UEDVT and were treated with a DOAC. We studied 61 patients, treated in six Italian centres between January 2014 and December 2018. Treatment lasted at least 3 months in all patients. In terms of efficacy, no recurrence of thrombosis or pulmonary embolism were recorded, while Doppler ultrasonography, performed after at least three months of treatment, documented in all cases either partial or complete recanalization of obstructed veins. In terms of safety, no cases of major bleedings were recorded. This is the only series available in the literature of patients treated with DOACs for UEDVT not associated with cancer and/or CVC. This small multicenter real world experience supports the concept that DOACs might be safe and effective for treating UEDTV. Further studies are required to better understand the role of DOACs in these patients.

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.

Predictors of Early Mortality in Cancer-Associated Thrombosis: Analysis of the RIETE Database.

Cancer-associated thrombosis (CT) carries a high, heterogeneous, and poorly predicted likelihood of mortality. Thus, we aimed to define predictors of 30-day mortality in 10,025 patients with CT. In a randomly selected derivation cohort, we used recursive partitioning analysis to detect variables that select for a risk of mortality within 30 days. In a validation cohort, we evaluated our results using Cochran-Armitage test. The most common types of cancer were lung (16%), breast (14%), and colorectal (14%); median age was 69 years (range, 14-101); most had metastatic disease (63%); 13% of patients died within 30 days. In the derivation cohort ( n = 6,660), a white blood cell (WBC) count in the highest quartile predicted early mortality (odds ratio, 7.8; 95% confidence interval [CI], 4.6-13.1); and the presence of metastatic disease, pulmonary embolism (PE), and immobility defined the risk of those with normal WBC count. We defined death risk according four sequential questions: (1) Does the patient have an elevated WBC count? (Yes, group D). (2) If no, does the patient have metastasis? (No, group A). (3) If yes, is the patient immobile? (Yes, group D). (4) If no, does the patient have a PE? (Yes, group C; no, group B). In the validation cohort ( n = 3,365), the 30-day risk of death was 2.9% in group A (95% CI, 1.9-4.3), compared with 25% in group D (95% CI, 22.5-27.5), and there was a rate escalation between groups ( p for trend < 0.01). In conclusion, with four sequential questions, the risk of death in CT can be easily stratified. An elevated WBC count at baseline predicted 30-day mortality better than metastases, PE, or immobility.

Uterine bleeding during anticoagulation in women with venous thromboembolism.

BACKGROUND: Women presenting with uterine bleeding during the course of anticoagulant therapy for venous thromboembolism (VTE) present a difficult therapeutic dilemma due to the absence of evidence-based recommendations. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to assess the clinical characteristics of women presenting with uterine bleeding during anticoagulation for VTE, its frequency, time course, management and 30-day outcomes. RESULTS: As of October 2016, 31,951 women with VTE were recruited in RIETE. During the course of anticoagulant therapy, 53 (0.17%) developed major uterine bleeding, 118 (0.37%) non-major uterine bleeding and 948 (2.97%) had major bleeding in other sites. Median time elapsed from VTE to bleeding was: 32, 71 and 22 days, respectively. Mean age was: 56±17, 52±20 and 75±14 years, respectively. Women with major uterine bleeding more likely had cancer (51%), anemia (72%), raised platelet count (19%) or recent major bleeding (11%) at VTE presentation than those in the other subgroups. During the first 30 days after bleeding, 17%, 1.7% and 31% of women died, respectively. Of 11 women with uterine bleeding who died, 9 (82%) had cancer, two (18%) died of bleeding and one (9.1%) died of pulmonary embolism after discontinuing anticoagulation. CONCLUSIONS: Uterine bleeding during the course of anticoagulation for VTE is not uncommon and mostly affects young women. Those with cancer, anaemia, raised platelet count or recent bleeding at baseline are at an increased risk for uterine bleeding during anticoagulation.

Predictors of active cancer thromboembolic outcomes. RIETE experience of the Khorana score in cancer-associated thrombosis.

Even though the Khorana risk score (KRS) has been validated to predict against the development of VTE among patients with cancer, it has a low positive predictive value. It is also unknown whether the score predicts outcomes in patients with cancer with established VTE. We selected a cohort of patients with active cancer from the RIETE (Registro Informatizado Enfermedad TromboEmbolica) registry to assess the prognostic value of the KRS at inception in predicting the likelihood of VTE recurrences, major bleeding and mortality during the course of anticoagulant therapy. We analysed 7948 consecutive patients with cancer-associated VTE. Of these, 2253 (28 %) scored 0 points, 4550 (57 %) 1-2 points and 1145 (14 %) scored ≥3 points. During the course of anticoagulation, amongst patient with low, moderate and high risk KRS, the rate of VTE recurrences was of 6.21 (95 %CI: 4.99-7.63), 11.2 (95 %CI: 9.91-12.7) and 19.4 (95 %CI: 15.4-24.1) events per 100 patient-years; the rate of major bleeding of 5.24 (95 %CI: 4.13-6.56), 10.3 (95 %CI: 9.02-11.7) and 19.4 (95 %CI: 15.4-24.1) bleeds per 100 patient-years and the mortality rate of 25.3 (95 %CI: 22.8-28.0), 58.5 (95 %CI: 55.5-61.7) and 120 (95 %CI: 110-131) deaths per 100 patient-years, respectively. The C-statistic was 0.53 (0.50-0.56) for recurrent VTE, 0.56 (95 %CI: 0.54-0.59) for major bleeding and 0.54 (95 %CI: 0.52-0.56) for death. In conclusion, most VTEs occur in patients with low or moderate risk scores. The KRS did not accurately predict VTE recurrence, major bleeding, or mortality among patients with cancer-associated thrombosis.

Prioritization of treatments for lower extremity peripheral artery disease in low- and middle-income countries.

INTRODUCTION: Lower extremity peripheral artery disease (PAD) is increasing in prevalence in low- and middle-income countries creating a large health care burden. Clinical management may require substantial resources but little consideration has been given to which treatments are appropriate for less advantaged countries. EVIDENCE ACQUISITION: The aim of this review was to systematically appraise published data on the costs and effectiveness of PAD treatments used commonly in high-income countries, and for an international consensus panel to review that information and propose a hierarchy of treatments relevant to low- and middle-income countries. EVIDENCE SYNTHESIS: Pharmacotherapy for intermittent claudication was found to be expensive and improve walking distance by a modest amount. Exercise and endovascular therapies were more effective and exercise the most cost-effective. For critical limb ischemia, bypass surgery and endovascular therapy, which are both resource intensive, resulted in similar rates of amputation-free survival. Substantial reductions in cardiovascular events occurred with use of low cost drugs (statins, ACE inhibitors, anti-platelets) and smoking cessation. CONCLUSIONS: The panel concluded that, in low- and middle-income countries, cardiovascular prevention is a top priority, whereas a lower priority should be given to pharmacotherapy for leg symptoms and revascularisation, except in countries with established vascular units.

Patterns and determinants of use of pharmacological therapies for intermittent claudication in PAD outpatients: results of the IDOMENEO study.

BACKGROUND: Peripheral arterial disease (PAD) usually presents with intermittent claudication (IC). The aim of the present study was to assess, in clinical practice, the pattern of use of pharmacological therapies for IC in stable PAD outpatients. METHODS: A propensity analysis was performed using data from the IDOMENEO study, an observational prospective multicenter cohort study. The association between any pharmacological symptomatic IC therapy with different variables was investigated using generalized linear mixed models with pharmacological therapy as response variable and binomial error. RESULTS: Study population: 213 patients, male sex 147 (69.0%), mean age 70.0±8.6 years. Only 36.6% was under pharmacological treatment for IC, being cilostazol the most used medication (21.6%). Univariate analysis showed a probability of a patient of being assigned to any pharmacological symptomatic IC therapy of 67.0% when Ankle-Brachial Index (ABI) <0.6 and 29.8% when ABI>0.6 (P=0.0048), and a propensity to avoid pharmacological treatment for patients with a high number of drugs to treat cardiovascular risk factors (probability of 55.2% for <4 drugs and 19.6% for >4 drugs, P=0.0317). Multivariate analysis confirmed a higher probability of assigning treatment for ABI<0.6 (P=0.0274), and a trend to a lower probability in patients under polypharmacy (>4 drugs: OR=0.13, P=0.0546). CONCLUSIONS: In clinical practice, only one third of stable outpatients with IC used symptomatic pharmacological therapy for IC. We found a propensity of clinicians to assign any symptomatic pharmacological IC therapy to patients with lower values of ABI and a propensity to avoid this kind of treatment in patients under polypharmacy.

Extensive Computed Tomography versus Limited Screening for Detection of Occult Cancer in Unprovoked Venous Thromboembolism: A Multicenter, Controlled, Randomized Clinical Trial.

Patients with unprovoked venous thromboembolism (VTE) may harbor occult cancer. Whether an extensive diagnostic work-up for cancer has additional value over a more limited screening for detection of underlying malignancy in these patients is controversial. We performed a randomized multicenter trial to assess if in patients with unprovoked VTE, a computed tomography (CT)-based diagnostic strategy including thoracic, abdominal, and pelvic CT in combination with fecal occult blood test yields a higher cancer detection rate than a nonstandardized testing approach based on physicians' clinical judgment and patients' preferences. Cancer-free patients were followed up for up to 24 months. Of the 195 consecutive patients with unprovoked VTE who were eligible for this investigation, an occult cancer was identified in 10 of the 98 patients (10.2%) randomized to the CT-based strategy, and in 8 of the 97 (8.2%) allocated to the personalized strategy (absolute difference, 2.0%; 95% confidence interval, -7.2-11.1; p = 0.81). During follow-up, cancer was identified in an additional 2 patients in each group. Overall, 7 (7.1%) patients of the CT-based strategy died, as compared with 11 (11.3%) of the personalized strategy, with 2 and 4, respectively, due to cancer. In conclusion, a CT-based strategy in combination with fecal occult blood test does not provide a clinically significant benefit over more limited cancer screening for detecting occult cancer in patients with unprovoked VTE. (ClinicalTrials.gov number, NCT00361647).

A prospective multicentre study on the treatment of cardiovascular risk factors and claudication symptoms in patients with peripheral artery disease (the IDOMENEO study).

BACKGROUND: The objective of this prospective multicenter cohort study was to characterise the use of pharmacological and non-pharmacological treatment for cardiovascular disease (CVD) risk factors and intermittent claudication (IC) symptoms in clinical practice patients with peripheral artery disease (PAD), and to determine the care gap with international guidelines and evidence-based therapy. PATIENTS AND METHODS: From 2011 through 2013, participating centres enrolled consecutive patients with PAD of atherosclerotic, origin demonstrated by ultrasound, ankle brachial index (ABI) < 0.9 and symptoms of IC. A seven item grid was built for the assessment of care gap (percentage of patients eligible for a treatment who did not receive it). cerebrovascular disease or at least two CVD risk factors. Care gap was lower than 25 % for any method to stop smoking, lipid lowering agents, antiplatelet and/or anticoagulation therapy and any kind of exercise program; between 25% and 50% for ACE inhibitors/ angiotensin II antagonist therapy; between 50% and 75% for beta-blocker therapy; and higher than 75% for supervised exercise program and use of cilostazol. Patients with and without CADI cerebrovascular disease were differently treated with clopidogrel (27.3% and 4.8 %, p < 0.001), any antiplatelet/anticoagulant therapy (98.7% and 83.3 %, p <0.001) and beta-blockers (46.8% and 16.0%, p<0.001). RESULTS: All patients (232) presented at least one CVC risk factor, 90.2% at least two, and 91.5% had either established CAD or CONCLUSIONS: Many gaps with evidence-based recommendations are still present in the pattern of the use of pharmacological and non-pharmacological treatment for CVD risk factors and IC symptoms in clinical practice PAD patients.

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer.

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding.

Prevention of venous thromboembolism in patients with cancer: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET)(1).

BACKGROUND: Prevention of venous thromboembolism (VTE) in cancer patients remains controversial in most clinical settings. PURPOSE: The Italian Society for Haemostasis and Thrombosis (SISET) commissioned a project to develop clinical practice guidelines for the prevention of VTE in patients with malignancy. METHODS: Key questions concerning the prevention of VTE in patients with malignancy were formulated by a multidisciplinary working group consisting of experts in clinical medicine and research. After a systematic review and discussion of the literature, recommendations were formulated and graded according to the supporting evidence. For those questions for which the literature search did not find any definitive answers (due to absence of evidence, low quality evidence and/or contradictory evidence), a formal consensus method was used instead to issue clinical recommendations. RESULTS: The search for "VTE prevention" resulted in 1021 citations; 69 articles were selected and 24 were used for drafting clinical recommendations. Four areas were graded A to C: 1) Need of prevention (pharmacological and/or mechanical) in cancer patients undergoing major abdominal or pelvic surgery and in 2) those with an acute medical disease requiring hospitalization and who are bedridden. Avoid prevention in 3) cancer patients with a central venous catheter and 4) those on chemotherapy, radiotherapy or hormonal therapy, except patients with multiple myeloma treated with thalidomide/lenalidomide plus high-dose dexamethasone, and those with gastrointestinal or lung cancer. Six areas were considered to be clinically important, but lacked evidence from the literature and thus required a formal consensus (grade D): 1) need of prevention during chemo- radiotherapy or hormonal therapy in patients with previous VTE; 2) optimal duration of pharmacological prevention in patients who are hospitalized/bedridden for acute medical illness; 3) optimal duration of pharmacological prevention in patients undergoing major surgery other than abdominal and pelvic; 4) optimal duration of pharmacological prevention in myeloma patients receiving thalidomide plus dexamethasone; 5) presence of cerebral metastasis as a contraindication to pharmacological prevention; 6) prevention in cancer patients undergoing surgery by laparoscopic procedures lasting>30min. CONCLUSION: Results of the systematic literature review and an explicit approach to consensus techniques have led to recommendations for the most clinically important issues in the prevention of VTE in cancer patients.

Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia.

This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.