Adult breast, lung, pancreatic, upper and lower gastrointestinal cancer patients with hospitalized venous thromboembolism in the national French hospital discharge database.

BACKGROUND: Venous thromboembolism (VTE) and cancer are strongly associated. In France, evidence on patients with pancreatic, upper GI [gastrointestinal], lower GI, lung, or breast cancer-associated VTE and their hospital management is limited. The aims of this study were to provide data on the number of hospitalized VTE events among cancer patients, the patients' characteristics, and their hospital management to estimate the burden of disease and the hospital burden of cancer-related VTE and to provide guidance on research. METHODS: This longitudinal, observational, and retrospective study was based on the comprehensive hospital discharge database (PMSI). Adult patients (≥ 18 years old) hospitalized with a cancer of interest in 2016 and hospitalized (within 2 years with VTE (captured a as a principal, related, or significant associated diagnosis) were included in the study. RESULTS: We identified 340,946 cancer patients, of which 7.2% (24,433 patients) were hospitalized with VTE. The proportions of hospitalized VTE were 14.6% (3,237) for patients with pancreatic cancer, 11.2% (8,339) for lung cancer, 9.9% (2,232) for upper GI cancer, 6.7% (7,011) for lower GI cancer, and 3.1% (3,614) for breast cancer. Around two thirds of cancer patients with a hospitalized VTE had active cancer (with metastases and/or receiving chemotherapy during the six months prior to the index date): from 62% of patients with pancreatic cancer to 72% with breast cancer. Around a third of patients were admitted to the hospital through the emergency room, up to 3% of patients stayed in an intensive care unit. The average length of stay ranged from 10 (breast cancer) to 15 days (upper GI cancer). Nine (lower GI cancer) to 18% (pancreatic cancer) of patients died during the VTE hospital stay. CONCLUSIONS: The burden of cancer-associated VTE is substantial, both in terms of the number of patients affected and in the hospital use. These findings offer guidance on future research on VTE prophylaxis in a very high-risk population, particularly in patients with active cancer.

Prevention of venous thromboembolic events in patients with lower leg immobilization after trauma: Systematic review and network meta-analysis with meta-epsidemiological approach.

BACKGROUND: Lower limb trauma requiring immobilization is a significant contributor to overall venous thromboembolism (VTE) burden. The clinical effectiveness of thromboprophylaxis for this indication and the optimal agent strategy are still a matter of debate. Our main objective was to assess the efficacy of pharmacological thromboprophylaxis to prevent VTE in patients with isolated temporary lower limb immobilization after trauma. We aimed to estimate and compare the clinical efficacy and the safety of the different thromboprophylactic treatments to determine the best strategy. METHODS AND FINDINGS: We conducted a systematic review and a Bayesian network meta-analysis (NMA) including all available randomized trials comparing a pharmacological thromboprophylactic treatment to placebo or to no treatment in patients with leg immobilization after trauma. We searched Medline, Embase, and Web of Science until July 2021. Only RCT or observational studies with analysis of confounding factors including adult patients requiring temporary immobilization for an isolated lower limb injury treated conservatively or surgically and assessing pharmacological thromboprophylactic agents or placebo or no treatment were eligible for inclusion. The primary endpoint was the incidence of major VTE (proximal deep vein thrombosis, symptomatic VTE, and pulmonary embolism-related death). We extracted data according to Preferred Reporting Items for Systematic Reviews and Meta-analyses for NMA and appraised selected trials with the Cochrane review handbook. Fourteen studies were included (8,198 patients). Compared to the control group, rivaroxaban, fondaparinux, and low molecular weight heparins were associated with a significant risk reduction of major VTE with an odds ratio of 0.02 (95% credible interval (CrI) 0.00 to 0.19), 0.22 (95% CrI 0.06 to 0.65), and 0.32 (95% CrI 0.15 to 0.56), respectively. No increase of the major bleeding risk was observed with either treatment. Rivaroxaban has the highest likelihood of being ranked top in terms of efficacy and net clinical benefit. The main limitation is that the network had as many indirect comparisons as direct comparisons. CONCLUSIONS: This NMA confirms the favorable benefit/risk ratio of thromboprophylaxis for patients with leg immobilization after trauma with the highest level of evidence for rivaroxaban. TRIAL REGISTRATION: PROSPERO CRD42021257669.

Statistical controversies in clinical research: limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events-a meta-analysis.

Background: Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA. Materials and methods: We searched Medline, Cochrane, ClinicalTrials.gov databases and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (ORs) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of OR, by dividing the OR values obtained in open-label trials by those obtained in DB trials. Results: The literature-based meta-analysis included 166 trials (72 024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 [95% confidence interval (95% CI) 2.12-2.73; P < 0.001], but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P = 0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI 0.83-1.17). The corresponding ratio of OR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P < 0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials. Conclusions: Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

Individualized PK-based prophylaxis in severe haemophilia.

Over the past decades, haemophilia management has continually evolved, with prophylaxis now considered the treatment of choice. Prophylaxis primarily seeks to prevent bleeding and haemarthrosis episodes from occurring and avert the otherwise inevitable haemophilic arthropathy. Yet, numerous unanswered issues remain. These concern dose levels, dosing intervals, ways of integrating variability in bleeding phenotype, patient age, joint status, lifestyle, physical activity, treatment adherence and individual responses to FVIII or FIX concentrates. Individualized prophylaxis may thus be paramount. One crucial tool that may allow more accurate prophylaxis regimens to be implemented is the individual pharmacokinetic (PK) study. Therefore, physicians in charge of managing those living with haemophilia must be comfortable with PK profiling in order to be in a position to tailor patients' treatment, taking into account PK data, while minimizing patients' inconvenience, discomfort, as well as, possibly, treatment costs. For optimization of prophylaxis, recent development of recombinant molecules with more attractive PK properties, such as prolonged elimination half-life, increases the choice of dosing regimens, enabling decreased frequency of dosing for some, if deemed appropriate. For each patient, PK parameters can be determined, including trough levels, AUC, and time spent under a predefined threshold, with additional pharmacodynamic (PD) parameters possibly established by means of a global coagulation test like the thrombin generation test. Most importantly, target PK/PD parameters will need to consider clinical variables like patient age, body weight, joint status, treatment adherence, number of bleeding episodes, activity index or lifestyle.

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

AIMS: Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ). METHODS: Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM. RESULTS: The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily. CONCLUSION: The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.

Pharmacokinetic/pharmacodynamic model for unfractionated heparin dosing during cardiopulmonary bypass.

BACKGROUND: High-dose heparin is used during cardiopulmonary bypass (CPB) to prevent thrombosis in the circuits used for extracorporeal circulation. The aim of this study was, initially, to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to assess the variability of PK/PD parameters and their correlation with the results of the routine haemostatic test activated clotting time (ACT) and thereafter to develop a Bayesian estimator enabling an individualized dosing strategy. METHODS: Fifty consecutive patients undergoing cardiac surgery with CPB were included in the study. Heparin was administered as an initial bolus of 300 IU kg -1 followed by additional boluses of 5000 IU to maintain ACT <400 s. In total, 361 blood samples were collected. The PK and PD data were analysed using a non-linear mixed effect model. RESULTS: A two-compartment model with a linear elimination link to an E max model best described heparin anti-factor Xa activities and ACT. Covariate analysis showed that body weight was positively correlated with clearance and central compartment volume. Inclusion of body weight with these parameters decreased their variability by 11 and 15%, respectively. The Bayesian estimator performed well in predicting individual parameters in an independent group of patients. CONCLUSIONS: A population PK/PD analysis of heparin during CPB, using a routine haemostatic test, shows that Bayesian estimation might help to predict ACT on the basis of only one or two blood samples.

Impairment of quality of life in patients with antiphospholipid syndrome.

OBJECTIVES: Health-related quality of life (HRQoL) has not been fully explored in antiphospholipid syndrome (APS); therefore, we compared HRQoL between APS patients and the general population and assessed the impact of thromboembolic history. METHODS: HRQoL was measured in a multicentre cohort study by the Medical Outcomes Study Short-Form 36 (MOS-SF-36) questionnaire. HRQoL scores were compared to the French general population norms. Factors significantly associated with an impaired HRQoL were identified. RESULTS: A total of 115 patients with aPL and/or systemic lupus erythematosus (SLE) were included (mean age 42.7 ± 14.1 years old, 86 women). In 53 patients APS was diagnosed. Compared to general population norms, patients with APS had an impaired HRQoL. SLE-associated APS patients had the worst HRQoL scores (physical component summary (PCS)=40.8 ± 10.6; mental component summary (MCS)=40.6 ± 16.5) in comparison with SLE or aPL patients without thromboembolic history. In APS patients, history of arterial thrombosis significantly impaired HRQoL (PCS score: 42.2 ± 9.4 vs 49.2 ± 8.5; MCS score: 33.9 ± 13.7 vs 44.6 ± 10.3). CONCLUSION: Compared to the general population, APS patients experienced a lower HRQoL. In these patients, a history of arterial thrombosis significantly impaired HRQoL. Therefore, measurements of HRQoL should be included in APS patient management to assess the burden of the disease from a patient's perspective and to provide patients with the support they need.

[Translation into French and republication of: "Management of cancer-associated thromboembolism in vulnerable population"]. / Traduction et republication de : « Prise en charge de la maladie thromboembolique veineuse associée au cancer chez les populations vulnérables ¼.

Although all patients with cancer-associated thrombosis (CAT) have a high morbidity and mortality risk, certain groups of patients are particularly vulnerable. This may expose the patient to an increased risk of thrombotic recurrence or bleeding (or both), as the benefit-risk ratio of anticoagulant treatment may be modified. Treatment thus needs to be chosen with care. Such vulnerable groups include older patients, patients with renal impairment or thrombocytopenia, and underweight and obese patients. However, these patient groups are poorly represented in clinical trials, limiting the available data on which treatment decisions can be based. Meta-analysis of data from randomised clinical trials suggests that the relative treatment effect of direct oral factor Xa inhibitors (DXIs) and low molecular weight heparin (LMWH) with respect to major bleeding could be affected by advanced age. No evidence was obtained for a change in the relative risk-benefit profile of DXIs compared to LMWH in patients with renal impairment or of low body weight. The available, albeit limited, data do not support restricting the use of DXIs in patients with TAC on the basis of renal impairment or low body weight. In older patients, age is not itself a critical factor for choice of treatment, but frailty is such a factor. Patients over 70 years of age with CAT should undergo a systematic frailty evaluation before choosing treatment and modifiable bleeding risk factors should be addressed. In patients with renal impairment, creatine clearance should be assessed and monitored regularly thereafter. In patients with an eGFR less than 30mL/min/1.72m2, the anticoagulant treatment may need to be adapted. Similarly, platelet count should be assessed prior to treatment and monitored regularly. In patients with grade 3-4, thrombocytopenia (less than 50,000platelets/µL) treatment with a LMWH at a reduced dose should be considered. For patients with CAT and low body weight, standard anticoagulant treatment recommendations are appropriate, whereas in obese patients, apixaban may be preferred.

[Translation into French and republication of: "Anticoagulant treatment of cancer-associated thromboembolism"]. / Traduction et republication de : « Traitement anticoagulant de la maladie veineuse thromboembolique associée au cancer ¼.

Venous thromboembolism (VTE) is a frequent and potentially fatal complication in patients with cancer. During the initial period after the thromboembolic event, a patient receiving anticoagulant treatment is exposed both to a risk of VTE recurrence and also to an elevated bleeding risk conferred by the treatment. For this reason, the choice of anticoagulant is critical. The choice should take into account patient-related factors (such as functional status, age, body mass index, platelet count and renal function), VTE-related factors (such as severity or site), cancer-related factors (such as activity and progression) and treatment related factors (such as drug-drug interactions), which all potentially influence bleeding risk, and patient preference. These should be evaluated carefully for each patient during a multidisciplinary team meeting. For most patients, apixaban or a low molecular-weight heparin is the most appropriate initial choice for anticoagulant treatment. Such treatment should be offered to all patients with active cancer for at least 6months. The patient and treatment should be re-evaluated regularly, and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond 6months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first 6months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

Antipsychotics: a real or confounding risk factor for venous thromboembolism?

In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.

Clinical presentation and outcome of venous thromboembolism in COPD.

Chronic obstructive pulmonary disease (COPD) is a moderate risk factor for venous thromboembolism (VTE), but neither the clinical presentation nor the outcome of VTE in COPD patients is well known. The clinical presentation of VTE, namely pulmonary embolism (PE) or deep venous thrombosis (DVT), and the outcome at 3 months (death, recurrent VTE or bleeding) were compared between 2,984 COPD patients and 25,936 non-COPD patients included in the RIETE (Registro Informatizado de la Enfermedad TromboEmbólica) registry. This ongoing international, multi-centre registry includes patients with proven symptomatic PE or DVT. PE was the more frequent VTE presentation in COPD patients (n = 1,761, 59%). PE presentation was more significantly associated with COPD patients than non-COPD patients (OR 1.64, 95% CI 1.49-1.80). During the 3-month follow-up, mortality (10.8% versus 7.6%), minor bleeding (4.5% versus 2.3%) or first VTE recurrences as PE (1.5% versus 1.1%) were significantly higher in COPD patients than in non-COPD patients. PE was the most common cause of death. COPD patients presented more frequently with PE than DVT. It may explain the worse prognosis of COPD patients, with a higher risk of death, bleeding or VTE recurrences as PE compared with non-COPD patients. Further therapeutic options are needed.

[Skin toxicity related to Percutalgine(®): analysis of the French pharmacovigilance database]. / Toxicité cutanée liée à la Percutalgine(®) : analyse de la base nationale de pharmacovigilance.

BACKGROUND: Percutalgine(®) (dexamethasone acetate, salicylamide and hydroxyethyl salicylate) is a topical drug marketed for treatment of benign joint conditions such as mild tendinitis, small joint arthritis and sprains. The aim of the study was to describe the cutaneous side effects of Percutalgine(®) in terms of clinical signs, seriousness and causal relationship of the different components. METHODS: We extracted from the French Pharmacovigilance database all cases of adverse skin reactions occurring after application of Percutalgine(®) and reported for the period between 1st January 2000 and 31st October 2010. The only files selected were those in which Percutalgine(®) was the sole suspected drug and/or allergological tests were positive for Percutalgine(®) or its components. RESULTS: Fifty-three cases were ultimately retained and analysed. The main cutaneous side effect of Percutalgine(®) (n=41) was contact dermatitis with secondary extension in 15 cases. Onset was immediate in 12 cases, delayed in 32 cases and unspecified in eight cases. Twelve patients were hospitalized for inefficiency of the symptomatic treatment, extended lesions or generalized associated signs. Allergological tests were described in 14 cases and were positive for Percutalgine(®) (eight cases), hydroxyethyl salicylate (seven cases), salicylamide (six cases), dexamethasone (three cases), and propylene glycol (two cases). CONCLUSION: Cutaneous side effects with Percutalgine(®) appear to be rare or infrequently reported. They consist chiefly of contact allergy. The component responsible for the reaction can be determined using allergological patch tests.

Twice- or Once-Daily Dosing of Direct Oral Anticoagulants, a systematic review and meta-analysis.

AIM: The direct oral anticoagulants (DOAC) have similar half-lives, but the dosing regimen varies between once daily (QD) or twice daily (BID). For some prescribers, the QD regimen improves compliance. Others prefer BID regimens to promote better stability of plasma concentrations, particularly in the event of missed doses. Limited level of evidence provides guidance about the best treatment strategy. The purpose of this study was to compare the treatment effect of QD vs. BID administration of DOACs in major orthopedic surgery (MOS), non-valvular atrial fibrillation (NVAF), venous thromboembolism (VTE), and acute coronary syndrome (ACS). METHODS: We conducted a systematic review up to April 2020. We included phase II clinical trials comparing DOAC QD vs BID with same daily dose. We extracted data for the occurrence of major thrombosis (proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke) and major hemorrhage (ISTH criteria and recommendations of the European Medicines Agency for surgical patients). Relative risks (RR) were combined using a fixed and random effects weighted meta-analysis. RESULTS: Twelve randomized, controlled, phase II trials were included (10,716 patients), representing 24 dosing regimen comparisons of apixaban, darexaban, edoxaban, rivaroxaban, letaxaban, and dabigatran. There was no difference for major thrombotic event (RRBID/QD = 1.06, 95%IC 0.86-1.30) nor for major bleeding (RRBID/QD = 1.02, 95%IC 0.84-1.23) between the BID vs QD regimens, without heterogeneity (I2 = 0%). CONCLUSION: Our study does not support a global difference in term of efficacy and safety of the BID and QD regimens of DOAC in MOS, NVAF, VTE and ACS.

Tranexamic acid in hip fracture surgery: a randomized controlled trial.

BACKGROUND: Hip fracture surgery may be associated with substantial blood loss. This study was designed to assess the efficacy and safety of the use of tranexamic acid in hip fracture surgery for the reduction of erythrocyte transfusion. METHODS: The study pertains to a randomized double-blind study with blinded adjudication of outcomes. Patients requiring surgery for an isolated hip fracture of less than 48 h received saline or tranexamic acid 15 mg kg(-1) given at skin incision and 3 h later. Primary efficacy outcome was erythrocyte transfusion from surgery up to day 8. Transfusion was administered according to a standardized protocol (Hb<9 g dl(-1)). Safety criterion was a composite of symptomatic and asymptomatic vascular events up to 6 weeks. RESULTS: Fifty-seven patients were randomized to tranexamic acid and 53 to placebo. The rate of erythrocyte transfusion was 42% with tranexamic acid and 60% with placebo (P=0.06). Preoperative haemoglobin value, age, and type of surgery were risk factors for erythrocyte transfusion independent of treatment group. The probability of vascular events at 6 weeks was 16% in the tranexamic acid group and 6% in the placebo group (P=0.10). A meta-analysis combining this study with previous trials showed that tranexamic acid significantly reduced erythrocyte transfusion in hip fracture surgery although efficacy was lower than that observed in hip or knee arthroplasty. CONCLUSIONS: In hip fracture surgery, tranexamic acid reduces erythrocyte transfusion but may promote a hypercoagulable state. Thus, further evaluation of safety is required before recommending the off-label use of tranexamic acid.

2008 SOR guidelines for the prevention and treatment of thrombosis associated with central venous catheters in patients with cancer: report from the working group.

BACKGROUND: In view of the lack of recommendations on central venous catheter (CVC)-associated thrombosis in cancer patients, we established guidelines according to the well-standardized Standards, Options and Recommendations methodology. MATERIAL AND METHODS: A literature review (1990-2007) on CVC-associated thrombosis was carried out. The guidelines were developed on the basis of the corresponding levels of evidence derived from analysis of the 36 of 175 publications selected. They were then peer reviewed by 65 independent experts. RESULTS: For the prevention of CVC-associated thrombosis, the distal tip of the CVC should be placed at the junction between the superior cava vein and right atrium; anticoagulants are not recommended. Treatment of CVC-associated thrombosis should be based on the prolonged use of low-molecular weight heparins. Maintenance of the catheter is justified if it is mandatory, functional, in the right position, and not infected, with a favorable clinical evolution under close monitoring; anticoagulant treatment should then be continued as long as the catheter is present. CONCLUSIONS: Several rigorous studies do not support the use of anticoagulants for the prevention of CVC-associated thrombosis. Treatment of CVC-associated thrombosis relies on the same principles as those applied in the treatment of established thrombosis in cancer patients.