Challenges Faced and Lessons Learned from Our Trial of VTE Prophylaxis.

Challenges and Lessons from Our VTE Prophylaxis TrialIn this Clinical Trials Case Study, the authors describe the challenges faced and lessons learned conducting a trial of venous thromboembolism prophylaxis among hospitalized older adults.

Enoxaparin versus Placebo to Prevent Symptomatic Venous Thromboembolism in Hospitalized Older Adult Medical Patients.

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Validation of risk assessment models predicting venous thromboembolism in acutely ill medical inpatients: A cohort study.

BACKGROUND: Because hospital-acquired venous thromboembolism (VTE) represents a frequent cause of preventable deaths in medical inpatients, identifying at-risk patients requiring thromboprophylaxis is critical. We aimed to externally assess the Caprini, IMPROVE, and Padua VTE risk scores and to compare their performance to advanced age as a stand-alone predictor. METHODS: We performed a retrospective analysis of patients prospectively enrolled in the PREVENU trial. Patients aged 40 years and older, hospitalized for at least 2 days on a medical ward were consecutively enrolled and followed for 3 months. Critical ill patients were not recruited. Patients diagnosed with VTE within 48 hours from admission, or receiving full dose anticoagulant treatment or who underwent surgery were excluded. All suspected VTE and deaths occurring during the 3-month follow-up were adjudicated by an independent committee. The three scores were retrospectively assessed. Body mass index, needed for the Padua and Caprini scores, was missing in 44% of patients. RESULTS: Among 14 910 eligible patients, 14 660 were evaluable, of which 1.8% experienced symptomatic VTE or sudden unexplained death during the 3-month follow-up. The area under the receiver operating characteristic curves (AUC) were 0.60 (95% confidence interval [CI] 0.57-0.63), 0.63 (95% CI 0.60-0.66) and 0.64 (95% CI 0.61-0.67) for Caprini, IMPROVE, and Padua scores, respectively. None of these scores performed significantly better than advanced age as a single predictor (AUC 0.61, 95% CI 0.58-0.64). CONCLUSION: In our study, Caprini, IMPROVE, and Padua VTE risk scores have poor discriminative ability to identify not critically ill medical inpatients at risk of VTE, and do not perform better than a risk evaluation based on patient's age alone.

Blood anti-Müllerian hormone is a possible determinant of recurrent early miscarriage, yet not conclusive in predicting a further miscarriage.

RESEARCH QUESTION: Is blood anti-Müllerian hormone (AMH) concentration a strong determinant of unexplained recurrent early miscarriage (REM)? DESIGN: In the first part of the study, AMH concentrations measured using an Immunotech ELISA Kit were compared between 188 unselected (mostly fertile) women consecutively referred for three or more miscarriages in the first trimester of pregnancy and 376 age-matched parous women without pregnancy loss. Cases and controls were previously enrolled in an incident case-control study on thrombophilic mutations. Blood samples were collected >2 months after any recognized obstetric event or hormonal treatment. In the second part of the study, a prospective 2-year follow-up of cases was performed. RESULTS: When considering all women irrespective of age, AMH concentration did not significantly differ between cases and controls. However, in the subgroup ≥25 years old (176 cases versus 358 controls of ∼33.5 years), the cases had significantly lower AMH concentrations than the controls (median [interquartile range]: 2.8 [1.4-4.7] versus 3.25 [1.7-5.5], P = 0.046) and the proportion of cases with an AMH concentration <1 ng/ml was significantly higher (17.6% versus 10.6%; odds ratio 1.80; 95% confidence interval 1.07-3.00, P = 0.028). With regard to the subsequent pregnancy, AMH concentration was not correlated with either the conception delay or the miscarriage occurrence. However, increased age and number of previous miscarriages were significantly predictive of a subsequent miscarriage (P = 0.046 and 0.03, respectively). CONCLUSION: An altered ovarian reserve is a possible determinant of unexplained REM. However, AMH blood concentration predicts neither the delay nor the outcome of a subsequent pregnancy.

Patent Foramen Ovale and Ischemic Stroke in Patients With Pulmonary Embolism: A Prospective Cohort Study.

Background: Pulmonary embolism (PE) is associated with increased risk for ischemic stroke, but the underlying mechanism remains unclear. The authors hypothesized that paradoxical embolism through patent foramen ovale (PFO) should be the main mechanism. Objective: To determine the frequency of recent ischemic stroke in patients with symptomatic PE according to whether PFO was detected. Design: Prospective cohort study with masked assessment of stroke outcomes. (ClinicalTrials.gov: NCT01216423). Setting: 4 French hospital centers. Participants: 361 consecutive patients with symptomatic acute PE from 13 November 2009 through 21 December 2015. Intervention: Systematic contrast transthoracic echocardiography (TTE) and cerebral magnetic resonance imaging (MRI) within 7 days after enrollment. Measurements: Recent symptomatic or silent ischemic stroke was diagnosed on the basis of clinical examination and cerebral MRI showing a hypersignal on the trace diffusion-weighted image with reduction or pseudonormalization of apparent diffusion coefficient. Results: Contrast TTE was conclusive in 324 of 361 patients and showed PFO in 43 patients (13%). The median age was 66 years (interquartile range, 54 to 77 years). In total, 51% of patients (145/284) had associated deep venous thrombosis, 91% (279/306) had cardiovascular risk factors, and 10% (16/151) presented with arrhythmia (no difference between PFO and non-PFO groups). Cerebral MRI was conclusive in 315 patients. Recent ischemic stroke was more frequent in the PFO group than in the non-PFO group (9 of 42 patients [21.4%] vs. 15 of 273 patients [5.5%]; difference in proportions, 15.9 percentage points [95% CI, 4.7 to 30.7 percentage points]). Limitation: Because of inconclusive contrast TTE or MRI, 46 patients were excluded from analysis. Conclusion: Frequency of recent ischemic stroke in patients with symptomatic PE was higher in patients with PFO than in those without PFO. This finding supports the hypothesis that paradoxical embolism is an important mechanism of ischemic stroke in patients with PFO. Primary Funding Source: French Ministry of Health.

Hydroxychloroquine for prevention of recurrent miscarriage: study protocol for a multicentre randomised placebo-controlled trial BBQ study.

INTRODUCTION: Recurrent miscarriage (RM), defined by three or more consecutive losses during the first trimester of pregnancy, affects 1%-2% of fertile couples. Standard investigations fail to reveal any apparent cause in ~50% of couples. However, on the basis of animal models and clinical studies, several hypotheses have been put forward concerning underlying mechanisms of RM: altered ovarian reserve, progesterone defect, thrombotic and/or endothelial dysfunction and immunological disturbances. Nonetheless, no study has yet reached conclusive beneficial clinical evidence for a potential treatment in unexplained RM. Hydroxychloroquine (HCQ) is a molecule with extensive safety data during pregnancy. The pharmacological properties of HCQ (eg, antithrombotic, vascular protective, immunomodulatory, improved glucose tolerance, lipidlowering and anti-infectious) could be effective against some mechanisms of unexplained RM. Furthermore, eventhough clinical benefit of HCQ is suggested in prevention of thrombotic and late obstetric events in antiphospholipid (APL) syndrome, there are no data suggesting the benefit of HCQ in RM in the presence of APL antibodies. METHODS AND ANALYSIS: Taken all together and given the low cost of HCQ, the aim of this multicentre, randomised, placebo-controlled, double-blind study is to investigate whether HCQ would improve the live birth rate in women with RM, irrespective of maternal thrombophilic status: (1) no known thrombophilia, (2) inherited thrombophilia or (3) APL antibodies. The primary end point is a live and viable birth. After confirming eligibility and obtaining consent, 300 non-pregnant women will be randomised into two parallel groups for a daily oral treatment (HCQ 400 mg or placebo), initiated before conception and stopped at 10 weeks' gestation. If pregnancy does not occur after 1 year, the treatment will be stopped. ETHICS AND DISSEMINATION: Agreement from the French National Public Health and Drug Security Agency (160765A-22) and ethical approval from the Committee for the Protection of Persons of NORD-OUEST I (2016-001330-97) have been obtained. TRIAL REGISTRATION NUMBERS: NCT0316513; Pre-results.

Six months versus two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial.

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P<0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.

Real-world incidence of cancer following a first unprovoked venous thrombosis: Results from the EPIGETBO study.

BACKGROUND: Venous thromboembolism (VTE) can be the first manifestation of cancer; however, the current incidence of malignancy in unselected patients with first unprovoked VTE needs to be confirmed. MATERIAL AND METHODS: Between March 1st, 2013 and February 28th, 2015 we included and followed-up all patients living in the Brest district, France, who were seen in hospitals or the community for a first symptomatic unprovoked VTE event. The primary study outcome was the one-year incidence of cancer. RESULTS: 526 patients, mean age 66.6 ±â€¯18.1 years, 246 (46.8%) men, were included in the study. In the year following VTE, 26 patients were diagnosed with cancer, corresponding to a one-year cumulative incidence of cancer of 5.06% (95% CI 3.47-7.35). Age ≥60, smoking and pulmonary embolism were significantly associated with cancer diagnosis in multivariate analysis. Fifty percent of cancers were patent at the time of VTE diagnosis, mostly detected on CTPA (Computed Tomographic Pulmonary Angiography) performed for pulmonary embolism assessment. After excluding patients with patent cancer at VTE diagnosis, the one-year incidence of cancer was 2.65% (95% CI: 1.55-4.52); in multivariate analysis, only current smoking was independently associated with a significant 5.4-fold increased risk for cancer diagnosis (HR 5.40; 95% CI 1.31-22.27). No cancer was diagnosed in patients aged 50 years or younger. CONCLUSION: The one-year incidence of cancer after a first unprovoked VTE was 5.06%. Half of the cancers were diagnosed during the diagnosis procedure for pulmonary embolism using CTPA.

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial.

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33-9.99) for age 50-65 years, 4.70 (95% CI 1.78-12.40) for age >65 years, 2.06 (95% CI 1.14-3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15-4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.

Incidence and impact of atrial arrhythmias on thrombotic events in MPNs.

Atrial arrhythmias (AA) induce a high rate of thromboses and require vitamin K antagonists (VKA) or direct anticoagulants (DOAC) prescriptions. Essential thrombocythemia (ET) and polycythemia vera (PV) are also pro-thrombotic diseases. The prevention of thromboses is based on the association of cytoreductive drug and low-dose aspirin (LDA). We studied the incidence and complications of AA among patients with ET or PV. We identified 96/713 patients (13.5%) carrying AA. These patients were older (median 72.1 vs. 61.3 years old, p < 0.0001). In a case-control analysis, we observed that patients with AA had a higher frequency of cardiovascular risk factors (77/96, 80% vs. 61/96, 61%; p = 0.01). A higher incidence of thromboses before and after myeloproliferative neoplasm (MPN) diagnosis was seen in this group: 26/96, 27.1% vs. 14/96, 14.6% (p = 0.03) and 34/96, 35% vs. 18/96, 18.8% (p = 0.009). Most of the events were arterial (82 vs. 61%, p = 0.09). This translates into a shorter thrombosis-free survival (11.0 vs. 21.6 years, p = 0.01). Continuation of LDA in this situation exposed patients to more thrombotic events (p = 0.04) but VKA did not seem to be good anticoagulant drugs either. The association of AA and MPN is more frequent than expected. AA clearly increased the thrombotic risk of these patients. Anticoagulant drugs should be carefully managed between cardiologists and hematologists. Association of LDA and VKA or the role of DOAC in such population should be rapidly discussed to reduce the thrombotic rate.

Risk of recurrent venous thromboembolism in COPD patients: results from a prospective cohort study.

We aimed to assess the risk of recurrent venous thromboembolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) following cessation of anticoagulation therapy.In a prospective cohort of 1468 patients with a documented episode of VTE, followed for up to 5 years after cessation of anticoagulation therapy, the diagnosis of COPD was confirmed in 136. The main outcome was recurrent VTE. The secondary outcome was overall mortality. Univariate and multivariate analyses were performed to identify the risk factors of recurrence.Of the 1468 patients included, recurrent VTE was observed in 306 (34 with COPD and 272 without) during a median follow-up period of 36.5 months. The incidence rate of recurrent VTE was 9.1% (95% CI 6.5-12.8) for COPD patients and 7.0% (95% CI 6.2-7.9) for non-COPD patients. COPD was not associated with an increased risk of VTE recurrence on univariate or multivariate analyses (hazard ratio: 1.0 (95% CI 0.7-1.4)). The risk of death, adjusted for demographic and clinical characteristics, showed no increase in COPD patients, as compared to non-COPD patients.In patients with COPD who had an acute episode of VTE, the risk of recurrent VTE was not any higher than that in non-COPD patients.

Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms.

Direct oral anticoagulants (DOACs) have been approved to treat and prevent thrombotic events. However, they are not yet labeled for use in patients with active cancers. Myeloproliferative neoplasms (MPNs) are clonal chronic disorders with a high incidence of thrombotic events, for which low-dose aspirin (LDA) is the standard drug treatment. We analyzed efficacy and safety of DOACs prescription in patients treated for MPNs. An MPN database, the OBENE registry, was established at our institution. We collected biological and clinical data from diagnosis to last follow-up for every patient included in this study. Thrombotic and hemorrhagic events and hematologic evolutions were categorized as major events in the database. Of the 760 MPN patients in the OBENE registry, 25 (3.3%) were treated with a DOAC. Median follow-up duration was 2.1 years (0.12-4.3 years). The reasons for prescribing DOACs were atrial fibrillation and thrombotic events for 13 and 12 patients, respectively. We only observed one thrombotic event (4%) and three major hemorrhagic events (12%). A case-control study did not detect a significant difference in thrombotic or hemorrhagic events in patients treated with LDA and DOACs. These preliminary results suggest that DOACs may be highly efficient and safe for use in MPN patients.

Association between hospitalization for acute medical illness and VTE risk: A lower efficacy of thromboprophylaxis in elderly patients? Results from the EDITH case-control study.

INTRODUCTION: Whether the association between hospitalization and venous thromboembolism (VTE) is modified by the use of thromboprophylaxis in older patients remains insufficiently evaluated. Our objective was to estimate VTE risk associated with hospitalization for acute medical illness depending on prescription of pharmacological thromboprophylaxis, in two different age categories using a 75years cutoff. METHODS: Using a case-control design, we estimated the risk for symptomatic VTE associated with hospitalization for acute medical illness depending on prescription of pharmacological thromboprophylaxis in two different age categories using a 75 years cut-off. RESULTS: 750 symptomatic VTE cases and their 750 age and sex-matched controls were analyzed. A total of 145 cases (19.3%) and 91 controls (12.1%) were hospitalized for acute medical illness in the preceding 3months prior to inclusion in the study (p<0.001). Hospitalization for acute medical illness was associated with a 75% increase in VTE risk: OR 1.75 (95% CI: 1.32-2.33). In patients <75years, there was a 2-fold increase in VTE risk associated with hospitalization when thromboprophylaxis was not prescribed: OR 2.01 (95% CI: 1.11-3.62), whereas no association was found when thromboprophylaxis was prescribed: OR 0.93 (95% CI: 0.44-1.95). In patients ≥75years, VTE risk associated with hospitalization remained significant whether or not thromboprophylaxis was prescribed: OR 2.69 (95% CI 1.28-5.66) and OR 2.02 (95% CI: 1.01-4.03) respectively. CONCLUSION: Our results suggest that VTE prevention in acutely ill medical patients may be less effective in patients ≥75years. This finding needs to be addressed in further studies.

Long-term mortality in older patients discharged after acute decompensated heart failure: a prospective cohort study.

BACKGROUND: Data are available on short- and intermediate-term mortality rates after discharge for acutely decompensated heart failure (ADHF). However, few studies specifically addressed ADHF outcomes in patients aged 75 years or over, who contribute more than half of all ADHF admissions. Our objectives here were to estimate the long-term mortality of patients aged 75 years or over who were discharged after admission for ADHF and to identify factors, especially geriatric findings, independently associated with 2-year mortality. METHODS: This prospective cohort study in five French hospitals included consecutive patients aged 75 years or older and discharged after emergency-department admission for ADHF meeting Framingham criteria (N = 478; median age, 85 years; 68% female). Kaplan-Meier 1-year and 2-year survival curves were plotted. Admission characteristics independently associated with overall 2-year mortality were identified using multivariable Cox proportional-hazards regression. RESULTS: Mortality was 41.7% (95% confidence interval [95% CI], 37.2%-53.5%) after 1 year and 56.0% (95% CI, 51.5%-60.7%) after 2 years. By multivariable analysis, independent predictors of 2-year mortality were male sex (hazard ratio [HR], 1.36; 95% CI, 1.00-1.82), age >85 years (HR, 1.57; 95% CI, 1.19-2.07), higher number of impaired activities of daily living (HR, 1.11 per impaired item; 95% CI, 1.05-1.17), recent weight loss (HR, 1.61; 95% CI, 1.14-2.28), and lower systolic blood pressure (HR, 0.86 per standard deviation increase; 95% CI, 0.74-0.99). Creatinine clearance ≤30 mL/min showed a trend toward an association with 2-year mortality (HR, 1.36; 95% CI, 0.97-2.00). CONCLUSION: Functional impairment before admission is associated with higher long-term mortality in patients ≥75 years admitted for ADHF. This study focused on geriatric markers not traditionally collected in heart-failure patients but did not analyse all cardiologic parameters associated with outcomes in other studies. Nevertheless, our findings may contribute to identify those patients admitted for ADHF who have the worst prognosis.

JAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort.

Cancer incidence in patients with recurrent unprovoked venous thromboembolism (VTE) is much higher than after a first event, but the incidence of myeloproliferative neoplasms (MPN) in this situation is still unknown. We tested for JAK2V617F and calreticulin mutants, 372 DNA samples of patients treated for (VTR). Among these patients, 10 (2.7%) were carrying JAK2V617F mutation and none of them any of the calreticulin (CALR) mutations. Among the 19 patients who had VTE recurrence under vitamin K antagonists, 4 patients (21.0%) were positive for JAK2V617F. Despite the identification of JAK2V617F mutation, only three patients were diagnosed for MPN despite a median follow-up of 4 years. We showed that the screening for JAK2V617F not CALR mutations should be helpful in this indication especially if recurrence happened under VKA therapy.

Current incidence of venous thromboembolism and comparison with 1998: a community-based study in Western France.

In 1998 we estimated the incidence of venous thromboembolism (VTE) to be 1.8/1,000 per year. The aim of this study was to compare current VTE incidence to that observed in 1998. We prospectively recorded all cases of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) of the lower limbs diagnosed between March 1, 2013 and February 28, 2014 in hospitals and in the community, using the same method and geographic area than in 1998. The 2013 incidence rates of VTE were computed and compared with those of 1998 using age- and sex-specific standardised incidence ratios (SIRs). In 2013, we recorded 576 VTE cases (279 isolated DVT and 297 PE ± DVT). Among 367,911 inhabitants, the overall incidence of VTE was 1.57/1,000 (95 % CI 1.44-1.69). The overall VTE incidence was significantly lower in 2013 as compared with 1998: SIR 0.72 (95 % CI 0.67-0.79) as well as the incidence of isolated DVT: SIR 0.53 (95 % CI 0.47-0.60); conversely, the overall incidence of PE was unchanged: SIR 1.10 (95 % CI, 0.98-1.23) despite an increase in the incidence of isolated PE: SIR 1.29 (95 % CI, 1.10-1.52). In 1998, 4.4 % of PE cases were diagnosed using CTPA as compared with 73.7 % in 2013 (p < 0.001). In conclusion, between 1998 and 2013, the incidence of symptomatic DVT decreased. Conversely, we found no similar reduction in the incidence of symptomatic PE; whether this is due to changes in diagnostic tests and algorithms in the management of suspected PE requires further investigations.

Multifaceted Intervention to Prevent Venous Thromboembolism in Patients Hospitalized for Acute Medical Illness: A Multicenter Cluster-Randomized Trial.

BACKGROUND: Misuse of thromboprophylaxis may increase preventable complications for hospitalized medical patients. OBJECTIVES: To assess the net clinical benefit of a multifaceted intervention in emergency wards (educational lectures, posters, pocket cards, computerized clinical decision support systems and, where feasible, electronic reminders) for the prevention of venous thromboembolism. PATIENTS/METHODS: Prospective cluster-randomized trial in 27 hospitals. After a pre-intervention period, centers were randomized as either intervention (n = 13) or control (n = 14). All patients over 40 years old, admitted to the emergency room, and hospitalized in a medical ward were included, totaling 1,402 (712 intervention and 690 control) and 15,351 (8,359 intervention and 6,992 control) in the pre-intervention and intervention periods, respectively. RESULTS: Symptomatic venous thromboembolism or major bleeding (primary outcome) occurred at 3 months in 3.1% and 3.2% of patients in the intervention and control groups, respectively (adjusted odds ratio: 1.02 [95% confidence interval: 0.78-1.34]). The rates of thromboembolism (1.9% vs. 1.9%), major bleedings (1.2% vs. 1.3%), and mortality (11.3% vs. 11.1%) did not differ between the groups. Between the pre-intervention and intervention periods, the proportion of patients who received prophylactic anticoagulant treatment more steeply increased in the intervention group (from 35.0% to 48.2%: +13.2%) than the control (40.7% to 44.1%: +3.4%), while the rate of adequate thromboprophylaxis remained stable in both groups (52.4% to 50.9%: -1.5%; 49.1% to 48.8%: -0.3%). CONCLUSIONS: Our intervention neither improved adequate prophylaxis nor reduced the rates of clinical events. New strategies are required to improve thromboembolism prevention for hospitalized medical patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01212393.

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.