Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery.

BACKGROUND: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients. METHODS: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding. RESULTS: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding). CONCLUSIONS: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).

Cancer-associated thrombosis in patients with implanted ports: a prospective multicenter French cohort study (ONCOCIP).

The need to accurately identify cancer outpatients at high risk of thrombotic complications is still unmet. In a prospective, multicenter cohort study (ONCOlogie et Chambres ImPlantables [ONCOCIP]), consecutive adult patients with a solid tumor and implanted port underwent 12-month follow-up. Our primary objective was to identify risk factors for (1) catheter-related thrombosis, defined as ipsilateral symptomatic upper-limb deep-vein thrombosis with or without pulmonary embolism, and (2) venous thromboembolism other than catheter-related, defined as any symptomatic superficial- or deep-vein thrombosis (other than catheter-related) or pulmonary embolism, and incidental pulmonary embolism. All events were objectively confirmed and centrally adjudicated. Rate assessments integrated competing risk of death. Overall, 3032 patients were included (median age: 63 years; women: 58%). The most frequent cancer locations were breast (33.7%), lung (18.5%), and colorectal (15.6%), cancer being metastatic in 43.2% of patients. Most patients (97.1%) received chemotherapy. By 12 months, 48 (1.6%) patients had been lost to follow-up and 656 (24.6%) had died; 3.8% (n = 111) of patients had experienced catheter-related thrombosis, and 9.6% (n = 276) venous thromboembolism other than catheter-related. By multivariate analysis, use of cephalic vein for catheter insertion predicted catheter-related thrombosis, whereas ongoing antiplatelet therapy was protective; risk factors for venous thromboembolism other than catheter-related were advanced age, previous venous thromboembolism, cancer site, and low hemoglobin level or increased leukocyte count before chemotherapy. In conclusion, this large prospective cohort study showed a high rate of venous thromboembolism in patients with a solid tumor and implanted port. Risk factors for catheter-related thrombosis differed from those for venous thromboembolism not catheter-related. This trial was registered at www.clinicaltrials.gov as #NCT02025894.

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.

Predicting the dose of vancomycin in ICU patients receiving different types of RRT therapy: a model-based meta-analytic approach.

AIM: Previous pharmacokinetic (PK) studies have proposed various dosing regimens for vancomycin in intensive care unit (ICU) patients undergoing renal replacement therapy (RRT), but all are restricted to specific RRT modalities. To be useful in practice, a population PK model would need to predict vancomycin clearance during any RRT modality. Development of such a model is feasible using meta-analysis of published summarized estimates of vancomycin PK parameters. Our aims were: (i) to develop and validate a population PK model for vancomycin that takes into account any RRT modalities, and (ii) to predict vancomycin dosing for RRT patients in ICU. METHODS: Vancomycin pharmacokinetics were assumed to be two-compartmental, total body clearance being the sum of non-RRT clearance and RRT-induced clearance. Drug disposition and non-RRT clearance parameters were estimated by systematic review and meta-analysis of previously published parameter estimates. The relationship between RRT-induced clearance and RRT flowrate settings was assessed using a model-based meta-analysis. Prediction performances of the PK model were assessed using external data. RESULTS: The meta-analyses of disposition parameters, non-RRT clearance and RRT-induced clearance included 11, 6 and 38 studies (84 RRT clearance measurements) respectively. The model performed well in predicting external individual PK data. Individual vancomycin concentrations during RRT were accurately predicted using Bayesian estimation based solely on pre-RRT measurements. CONCLUSIONS: The PK model allowed accurate prediction of the vancomycin pharmacokinetics during RRT in ICU patients. Based on the model of RRT-induced clearance, an appropriate adjustment of the vancomycin dosing regimen could be proposed for any kind of flowrate settings.

High tolerance of progressive elastic compression in peripheral arterial disease.

Background: Theoretically progressive compression stockings, which produce a higher compression at the calf than at the ankle level, improve venous return flow without exacerbating peripheral arterial insufficiency (PAD). We aimed to evaluate the short-term tolerance of elastic progressive compression stockings on peripheral arterial vascularisation in patients with symptomatic PAD and associated mild venous insufficiency. Patients and methods: Monocentric, prospective, open pilot study of 18 patients (acceptability study, 6 x 6 plan) evaluating the short-term tolerance of progressive compression stockings (18 ± 2 mmHg at calf and 8 ± 2 mmHg at ankle level) in patients with PAD (ankle brachial index ABI > 0.60 < 0.75) and chronic venous insufficiency (C1s-C4 stages of the CEAP classification). Day 15 tolerance was evaluated by a composite primary criteria comprising: no decrease > 15 % of ABI on each side, no decrease > 15 % of toe brachial index (TBI) on each side and no decrease > 25 % of the number of active plantar flexions performed while standing. Results: The proportion of men was 77.8 %, mean age was 77.3 ± 7.5 years and no patient were diabetic. At inclusion, the mean low ABI was 0.60 ± 0.04 and the mean high ABI was 0.77 ± 0.18. The mean low TBI was 0.32 ± 0.09 and the mean high TBI 0.46 ± 0.15. The mean number of active standing plantar flexions was 33.0 ± 5.0. The majority of the patients were classified in CEAP C2s and C3 classes (class 2: 16.7 %, class C2s: 27.8 %, class C3: 44.4 %, class C4: 5.6 % and class C4s: 5.6 %). Poor tolerance occurred in no patient. By day 30, no patient had worsening of their arterial and venous symptoms. No adverse events occurred during the study. Conclusions: These results suggest a high tolerance of progressive elastic stockings (18 ± 2 mmHg at calf and 8 ± 2 mmHg at ankle level) in symptomatic PAD.

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.

Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: A meta-analysis of observational studies.

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be potentially associated with an increased risk of bleeding. A meta-analysis of observational studies was conducted to quantify this risk. Case-control and cohort studies investigating bleeding risk under SSRI therapy were retrieved by searching the Medline, Pascal, Google Scholar and Scopus databases. Case-control studies were included if they reported bleeding incidents with and without the use of SSRIs and cohort studies were included if they reported the rate of bleeds among SSRI users and non-users. The main outcome was severe bleeding, whatever the site. Only data concerning SSRI belonging to the ATC class N06AB were used. For both case-control and cohort studies, we recorded the adjusted effect estimates and their 95% confidence intervals (CI). Pooled adjusted odds ratio (OR) estimates were computed for case-control and cohort studies using an inverse-variance model. Meta-analysis of the adjusted ORs of 42 observational studies showed a significant association between SSRI use and the risk of bleeding [OR 1.41 (95% CI 1.27-1.57), random effect model, p<0.0001]. The association was found for the 31 case-control studies (1,255,073 patients), with an increased risk of 41% of bleeding [OR 1.41 (95% CI 1.25-1.60)], as well as for the 11 cohort studies including 187,956 patients [OR 1.36 (95% CI 1.12-1.64)]. Subgroup analyses showed that the association remained constant whatever the characteristics of studies. This meta-analysis shows an increased risk of bleeding of at least 36% (from 12% to 64%) based on the high-level of observational studies with SSRIs use.

Direct oral anticoagulants: Current indications and unmet needs in the treatment of venous thromboembolism.

The treatment of acute venous thromboembolism (VTE) is being completely modified with the development of direct oral anticoagulants (DOACs). Rivaroxaban, apixaban and edoxaban directly inhibit factor Xa, whereas dabigatran inhibits factor IIa. All these drugs are proposed orally, and share pharmacological similarities: fixed doses without any therapeutic drug monitoring, key role of the transporter proteins P-glycoprotein for all of them and metabolism mediated by CYP3A4 for the anti-Xa, short half-life with variable rate of renal elimination. More than 25 000 patients with acute VTE were included in phase-III studies. Rivaroxaban and apixaban challenged all the conventional therapy (parenteral heparins followed by anti-vitamin K antagonists) whereas edoxaban and dabigatran challenged only anti-vitamin K antagonists. All the DOACs met the non-inferiority efficacy endpoint (recurrent VTE during treatment), whereas the large non-inferiority margin was debated for dabigatran. However, they were associated with better safety and a decreased risk of major bleeding. According to indirect comparisons, there were no statistically significant differences between DOACs in terms of efficacy but some differences are not excluded in term of safety. Although DOACs allow for simplification of treatment in the majority of patients with acute VTE, their risk/benefit ratio is questioned in elderly patients, patients with mild-to-severe renal impairment, and in some clinical subgroups such as cancer or chronic thromboembolic pulmonary hypertension. Validated reversal strategies (potentially based on laboratory monitoring) are expected for patients with major bleeding, overdose or with a need for surgery.

[False positive results or what's the probability that a significant P-value indicates a true effect?] / Les résultats faux positifs ou quelle est la probabilité que le traitement soit efficace quand p < 0,05 ?

The use of statistical test is central in the clinical trial. At the statistical level, obtaining a P<0.05 allows to claim the effectiveness of the new studied treatment. However, given its underlying mathematical logic the concept of "P value" is often misinterpreted. It is often assimilated, mistakenly, to the likelihood that treatment is ineffective. Actually the "P value" gives an indirect information about the plausibility of the existence of treatment effect. With "P<0.05", the probability that the treatment is effective may vary depending on other statistical parameters which are the alpha level of risk, the power of the study and especially the a priori probability of the existence of treatment effect. A "P<0.05" does not always produce the same degree of certainty. Thus there exist situations where the risk of a result "P<0.05" is in reality a false positive is very high. This is the case if the power is low, if there is an inflation of the alpha risk or if the result is exploratory or chance discoveries. This possibility is important to take into consideration when interpreting the results of clinical trials in order to avoid pushing ahead significant results in appearance, but which are likely to be actually false positive results.

Clinical research and methodology: What usage and what hierarchical order for secondary endpoints?

In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.

Six Months vs Extended Oral Anticoagulation After a First Episode of Pulmonary Embolism: The PADIS-PE Randomized Clinical Trial.

IMPORTANCE: The optimal duration of anticoagulation after a first episode of unprovoked pulmonary embolism is uncertain. OBJECTIVES: To determine the benefits and harms of an additional 18-month treatment with warfarin vs placebo, after an initial 6-month nonrandomized treatment period on a vitamin K antagonist. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind trial (treatment period, 18 months; median follow-up, 24 months); 371 adult patients who had experienced a first episode of symptomatic unprovoked pulmonary embolism (ie, with no major risk factor for thrombosis) and had been treated initially for 6 uninterrupted months with a vitamin K antagonist were randomized and followed up between July 2007 and September 2014 in 14 French centers. INTERVENTIONS: Warfarin or placebo for 18 months. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months after randomization. Secondary outcomes were the composite at 42 months (treatment period plus 24-month follow-up), as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. RESULTS: After randomization, 4 patients were lost to follow-up, all after month 18, and 1 withdrew due to an adverse event. During the 18-month treatment period, the primary outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 (13.5%) in the placebo group (hazard ratio [HR], 0.22; 95% CI, 0.09-0.55; P = .001). Recurrent venous thromboembolism occurred in 3 patients in the warfarin group and 25 patients in the placebo group (HR, 0.15; 95% CI, 0.05-0.43); major bleeding occurred in 4 patients in the warfarin group and in 1 patient in the placebo group (HR, 3.96; 95% CI, 0.44 to 35.89). During the 42-month entire study period (including the study treatment and follow-up periods), the composite outcome occurred in 33 patients (20.8%) in the warfarin group and in 42 (24.0%) in the placebo group (HR, 0.75; 95% CI, 0.47-1.18). Rates of recurrent venous thromboembolism, major bleeding, and unrelated death did not differ between groups. CONCLUSIONS AND RELEVANCE: Among patients with a first episode of unprovoked pulmonary embolism who received 6 months of anticoagulant treatment, an additional 18 months of treatment with warfarin reduced the composite outcome of recurrent venous thrombosis and major bleeding compared with placebo. However, benefit was not maintained after discontinuation of anticoagulation therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740883.

Prevention of venous thromboembolic events with low-molecular-weight heparin in the non-major orthopaedic setting: meta-analysis of randomized controlled trials.

PURPOSE: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. METHODS: A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. RESULTS: Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). CONCLUSIONS: This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. LEVEL OF EVIDENCE: Level II, meta-analysis of Level II studies or Level I studies with inconsistent results.

[New oral anticoagulants: pharmacological data to know for clinical practice]. / Nouveaux anticoagulants oraux: données pharmacologiques a connaître pour la pratique clinique.

New oral anticoagulants target specific factors in the coagulation cascade by directly inhibiting thrombin for dabigatran and Factor Xa for -xatrans. Pharmacological progresses with these anticoagulants allow the use of fixed doses without any therapeutic drug monitoring. Their pharmacokinetic specificity is the key role of the transporter proteins P-glycoprotein (P-gp) for all these drugs and the metabolism mediated by CYP3A4 for -xabans. Dose adjustment is recommended for decreasing creatinine clearance or in case of drug-drug interaction. New oral anticoagulants are promising but their safety needs further investigations in particular populations such as elderly patients, patients with renal or hepatic impairment, or patients on polymedication.

A framework to characterise the reproducibility of meta-analysis results with its application to direct oral anticoagulants in the acute treatment of venous thromboembolism.

The number of meta-analyses of aggregate data has dramatically increased due to the facility of obtaining data from publications and the development of free, easy-to-use, and specialised statistical software. Even when meta-analyses include the same studies, their results may vary owing to different methodological choices. Assessment of the replication of meta-analysis provides an example of the variation of effect 'naturally' observed between multiple research projects. Reproducibility of results has mostly been reported using graphical descriptive representations. A quantitative analysis of such results would enable (i) breakdown of the total observed variability with quantification of the variability generated by the replication process and (ii) identification of which variables account for this variability, such as methodological quality or the statistical analysis procedures used. These variables might explain systematic mean differences between results and dispersion of the results. To quantitatively characterise the reproducibility of meta-analysis results, a bivariate linear mixed-effects model was developed to simulate both mean results and their corresponding uncertainty. Results were assigned to several replication groups, those assessing the same studies, outcomes, treatment indication and comparisons classified in the same replication group. A nested random effect structure was used to break down the total variability within each replication group and between these groups to enable calculation of an intragroup correlation coefficient and quantification of reproducibility. Determinants of variability were investigated by modelling both mean and variance parameters using covariates. The proposed model was applied to the example of meta-analyses evaluating direct oral anticoagulants in the acute treatment of venous thromboembolism.

Latest advances in the reversal strategies for direct oral anticoagulants.

BACKGROUND: Since the late 2000s, Europe has granted approval for various thrombotic risk-related uses of direct oral anticoagulants (DOACs). Unlike traditional anticoagulants, DOACs do not necessitate routine coagulation monitoring. Nevertheless, clinical practice often encounters bleeding events associated with these medications, making the need for effective reversal strategies evident. OBJECTIVES: The study aims to take stock of current reversal strategies for DOACs, with a particular emphasis on the latest compounds that have been developed or are currently under development. METHODS: For obtaining information regarding the ongoing reversal strategies and the compounds under development, we referred to ClinicalTrials website, PubMed, and Google Scholar. RESULTS: In 2024, two specific antidotes to DOACs have already received approval when reversal of anticoagulation is needed owing to life-threatening or uncontrolled bleeding: idarucizumab that reverses the effects of dabigatran, and andexanet alfa, designed to counteract activated factor X inhibitors such as apixaban and rivaroxaban. Furthermore, ciraparantag, a potential universal reversal agent, is currently in advanced stages of clinical development. Concerns remain regarding the safety of specific reversal agents, especially concerning the risk of thrombosis. Additionally, the cost of these antidotes remains high. Consequently, nonspecific strategies to counteract anticoagulant medications, including activated charcoal, hemodialysis, and concentrates of coagulation factors, still have utility. CONCLUSION: With the validation of specific and nonspecific antidotes, DOACs could supplant traditional oral anticoagulants. This progress represents a significant advancement in anticoagulation therapy. However, ongoing research is crucial to address remaining safety concerns of the specific reversion agents of DOACs in clinical practice.

Management of cancer-associated thromboembolism in vulnerable population.

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 CAT 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<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 (<50,000 platelets/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.

Anticoagulant treatment of cancer-associated thromboembolism.

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 six months. The patient and treatment should be re-evaluated regularly and anticoagulant treatment changed when necessary. Continued anticoagulant treatment beyond six months is justified if the cancer remains active or if the patient experienced recurrence of VTE in the first six months. In other cases, the interest of continued anticoagulant treatment may be considered on an individual patient basis in collaboration with oncologists.

Data Monitoring Committees and clinical trials: From scientific justification to organisation.

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied.