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.

Cancer-related arterial thromboembolic events.

Cancer is associated with a hypercoagulable state and is a well-known independent risk factor for venous thromboembolism, whereas the association between cancer and arterial thromboembolism is less well established. Arterial thromboembolism, primarily defined as myocardial infarction or stroke is significantly more frequent in patients with cancer, independently of vascular risk factors and associated with a three-fold increase in the risk of mortality. Patients with brain cancer, lung cancer, colorectal cancer and pancreatic cancer have the highest relative risk of developing arterial thromboembolism. Antithrombotic treatments should be used with caution due to the increased risk of haemorrhage, as specified in current practice guidelines.

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.

French guidelines for the treatment of cancer-associated venous thromboembolism - 2023 update.

BACKGROUND: In recent years, knowledge about cancer associated thrombosis has evolved considerably. METHODS: Practical guidelines were drafted on the initiative of the INNOVTE FCRIN Network, led by the French Speaking Society of Respiratory Diseases (SPLF), by a coordinating group, a writing group, and a review group, with the involvement of different scientific societies practicing in various settings. The method followed the "Clinical Practice Guidelines" process of the French National Authority for Health (HAS). RESULTS: After a literature review, guidelines were formulated, improved, and then validated by the working groups. These guidelines addressed multiple aspects of the disease and management from the data of available clinical trials and observational studies : epidemiology, initial treatment, treatment duration, extended treatment, recurrent thrombosis, central venous catheter thrombosis, incidental thrombosis, treatment in case of thrombocytopenia. CONCLUSION: These evidence-based guidelines are intended to guide the practical management of patients with cancer associated thrombosis.

Pulmonary embolism diagnostic strategies in patients with COPD exacerbation: Post-hoc analysis of the PEP trial.

BACKGROUND: The prevalence of pulmonary embolism (PE) is approximately 11-17 % in patients with an acute exacerbation of chronic obstructive pulmonary disease (AE-COPD). The optimal diagnostic strategy for PE in these patients remains undetermined. AIMS: To evaluate the safety and efficacy of standard (revised Geneva and Wells PE scores combined with fixed D-dimer cut-off) and computed tomography pulmonary angiogram (CTPA)-sparing diagnostic strategies (ADJUST-PE, YEARS, PEGeD, 4PEPS) in patients with AE-COPD. METHOD: Post-hoc analyses of data from the multicenter prospective PEP study were performed. The primary outcome was the diagnostic failure rate of venous thromboembolism (VTE) during the entire study period. Secondary outcomes included diagnostic failure rate of PE and deep venous thrombosis (DVT), respectively, during the entire study period and the number of CTPA needed per diagnostic strategy. RESULTS: 740 patients were included. The revised Geneva and Wells PE scores combined with fixed D-dimer cut-off had a diagnostic failure rate of VTE of 0.7 % (95%CI 0.3 %-1.7 %), but >70.0 % of the patients needed imaging. All CTPA-sparing diagnostic algorithms reduced the need for CTPAs (-10.1 % to -32.4 %, depending on the algorithm), at the cost of an increased VTE diagnosis failure rate of up to 2.1 % (95%CI 1.2 %-3.4 %). CONCLUSION: Revised Geneva and Wells PE scores combined with fixed D-dimer cut-off were safe, but a high number of CTPA remained needed. CTPA-sparing algorithms would reduce imaging, at the cost of an increased VTE diagnosis failure rate that exceeds the safety threshold. Further studies are needed to improve diagnostic management in this population.

Inhibition of Factor XI: A New Era in the Treatment of Venous Thromboembolism in Cancer Patients?

Direct oral anticoagulants against activated factor X and thrombin were the last milestone in thrombosis treatment. Step by step, they replaced antivitamin K and heparins in most of their therapeutic indications. As effective as the previous anticoagulant, the decreased but persistent risk of bleeding while using direct oral anticoagulants has created space for new therapeutics aiming to provide the same efficacy with better safety. On this basis, drug targeting factor XI emerged as an option. In particular, cancer patients might be one of the populations that will most benefit from this technical advance. In this review, after a brief presentation of the different factor IX inhibitors, we explore the potential benefit of this new treatment for cancer patients.

Plasma lipidomic analysis to investigate putative biomarkers of P-glycoprotein activity in healthy volunteers.

P-glycoprotein (P-gp) is an efflux transporter involved in the bioavailability of many drugs currently on the market. P-gp is responsible for several drug-drug interactions encountered in clinical practice leading to iatrogenic hospital admissions, especially in polypharmacy situations. ABCB1 genotyping only reflects an indirect estimate of P-gp activity. Therefore, it would be useful to identify endogenous biomarkers to determine the P-gp phenotype to predict in vivo activity prior to the initiation of treatment and to assess the effects of drugs on P-gp activity. The objective of this study was to assess changes in plasma lipidome composition among healthy volunteers selected on the basis of their ABCB1 genotype and who received clarithromycin, a known inhibitor of P-gp. Untargeted lipidomic analysis based on liquid chromatography-tandem mass spectrometry was performed before and after clarithromycin administration. Our results revealed changes in plasma levels of some ceramides (Cers) {Cer(d18:1/22:0), Cer(d18:1/22:1), and Cer(d18:1/20:0) by ~38% (p < 0.0001), 13% (p < 0.0001), and 13% (p < 0.0001), respectively} and phosphatidylcholines (PCs) {PC(17:0/14:1), PC(16:0/18:3), and PC(14:0/18:3) by ~24% (p < 0.001), 10% (p < 0.001), and 23.6% (p < 0.001)} associated with both ABCB1 genotype and clarithromycin intake. Through the examination of plasma lipids, our results highlight the relevance of untargeted lipidomics for studying in vivo P-gp activity and, more generally, to safely phenotyping transporters.

Primary prevention of cancer-associated venous thrombosis: Rationale and challenges in clinical practice.

Cancer-associated venous thrombosis (CAT) is a common, multifactor event known to complicate the course of cancer and jeopardize a patient's prognosis. The current guidelines regarding the prevention of CAT are sometimes considered insufficiently precise about specific situations, or are poorly applied. The expected benefits of thromboprophylaxis are balanced by the risk of major bleeding induced by anticoagulation, which implies a need to accurately identify ambulatory patients at high risk of thrombosis or hemorrhage. The Khorana score is commonly used for this, but is limited by the non-reproducibility of predicted performance across cancer types, and by the fact that antitumor treatment and cardiovascular risks are not included. The COMPASS-CAT score, which includes those two aspects, was found to be a more accurate predictor of venous thromboembolism in patients with lung cancer, and to better distinguish between patients at low or high risk of thrombosis. The frailty of patients with cancer is also a major issue, and should be taken into account when thromboprophylaxis is considered. According to current guidelines, CAT prophylaxis should be considered for hospitalized patients, those for whom surgery is scheduled, or those with pancreatic cancers. In ambulatory patients, decisions should be made according to patient, cancer and antitumoral treatment characteristics. Low molecular weight heparin is the gold standard of CAT prophylaxis. Despite increased risks of bleeding or drug-drug interactions in cancer patients, direct oral anticoagulants could be alternate options for high-risk ambulatory patients that should be accompanied by a careful global analysis of benefits, harms, and patient preferences.

Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

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

Enoxaparin to Prevent Venous Thromboembolism in Older AdultsThis 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.

Pulmonary Embolism in the Cancer Associated Thrombosis Landscape.

In cancer patients, pulmonary embolism (PE) is the second leading cause of death after the cancer itself, most likely because of difficulties in diagnosing the disease due to its nonclassical presentation. The risk of PE recurrence and possibly the case-fatality rate depends on whether the patient presents a symptomatic PE, an unsuspected PE, a subsegmental PE, or a catheter-related PE. Choosing the best therapeutic option is challenging and should consider the risk of both the recurrence of thrombosis and the occurrence of bleeding. The purpose of this review is to provide an overview of the clinical characteristics and the treatment of cancer-associated PE, which could benefit clinicians to better manage the deadliest form of thrombosis associated with cancer. After a brief presentation of the epidemiological data, we will present the current attitude towards the diagnosis and the management of cancer patients with PE. Finally, we will discuss the perspectives of how the medical community can improve the management of this severe medical condition.

Management of Cancer-Associated Thrombosis in France: A National Survey among Vascular Disease and Supportive Care Specialists.

Low molecular weight heparins (LMWHs) are recommended by international guidelines for at least 6 months in patients with cancer-associated thromboembolism (CAT). Direct oral anticoagulants (DOACs) have been proposed as an alternative to LMWH. In clinical practice, the specialists in charge of CAT have to decide which anticoagulant to prescribe. An electronic survey tool, including vignettes and questions, was sent to members of the French Society of Vascular Medicine, the French-speaking association for supportive care in oncology and the Investigation Network On Venous Thrombo-Embolism. Among the 376 respondents, LMWHs were reported as the first choice by most specialists. The prescription of DOACs within the first 3 weeks of CAT diagnosis was highly dependent on the cancer site: 5.9%, 18.6% and 24.5% in patients with locally advanced colorectal, lung and breast cancer, respectively. The determinants were mostly related to cancer (site and stage or evolution) and to anticancer treatments. For 61% of physicians, some anticancer treatments were contraindications to DOACs. However, almost 90% of physicians considered switching to DOAC after a median 3-month period of LMWHs. In daily practice, LMWHs and DOACs are now considered by specialists of CAT; the decision is mostly driven by the site of cancer. The role of anticancer treatments in the decision remains to be investigated.

Pathological Analysis and Clinical Evolution After Radiological Removal of Retrievable Vena Cava Filters.

OBJECTIVE: Retrievable inferior vena cava filters (IVCF) have been developed because permanent filters have been associated with an increased risk of recurrent deep venous thrombosis. There is no data on the interactions of IVCF with the inferior vena cava (intrafilter thrombi, insertion through the venous wall) even though this may alter the course after retrieval of the IVCF. METHODS: A review of 85 consecutive patients undergoing retrieval of IVCF placed at a single center was performed from January 1, 2010 and December 31, 2014. Inferior vena cava filter were examined for presence of intrafilter thrombus at time of retrieval. Filter position and presence of intraluminal thrombus were examined. Patient outcomes, including recurrence of deep vein thrombosis (DVT) and death, were captured at 3 month followup. RESULTS: Eighty five patients were identified, with intrafilter thrombi found in 69 (81%) patients and venous wall fragments found in 75 (88%) patients. However, their presence was not associated with an increased risk of recurrent venous thromboembolism (VTE) or death during follow up. CONCLUSIONS: Intrafilter thrombi and venous wall fragments are frequently found in removed IVCF but are not associated with a worse prognosis. They may not modify the therapeutic management of patients.

Frequency and predictors for chronic thromboembolic pulmonary hypertension after a first unprovoked pulmonary embolism: Results from PADIS studies.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined. OBJECTIVE: To determine the frequency and predictors for CTEPH after a first unprovoked PE. PATIENTS/METHODS: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated. RESULTS: During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01]). CONCLUSION: After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis.

Cardiac Biomarkers in Patients with Acute Pulmonary Embolism.

Pulmonary embolism is a frequent and potentially fatal disease. The major challenge of initial management lies in prognostic stratification. Since 2014, the European recommendations on the diagnosis and management of acute pulmonary embolism are based on assessing the risk stratification regarding hemodynamic status first, then on a combined risk assessment model using a clinical score, an imaging evaluation of right heart size and the concentration of a serum cardiac biomarker. Usual biomarkers cover cardiac ischemia (troponin and derivates) and dilatation (BNP and derivates). The aim of this review is to offer a practical update on the role of the Troponins and BNPs families of biomarkers and the prognosis of pulmonary embolism, and furthermore, to provide a brief overview of their place in current management.

Platelet transmission electron microscopy for the assessment of poor biological response to antiplatelet agent: pilot descriptive and prospective study - ELECTROSTROKE.

INTRODUCTION: Ischaemic stroke is the leading cause of adult disability. Thus, a strategy based on an efficient antiplatelet therapy has been developed. The monitoring of antiplatelet therapy is now limited to high risk and poor prognosis patients. Indeed, the biological monitoring of the antiplatelet therapy with available platelet function assays do not provide a global integrative approach. Platelet transmission electron microscopy, recently validated for assessing distinct ultrastructural abnormalities is a reliable morphological platelet structural analysis tool which could be used to collect all the ultrastructural platelet characteristics and assess the degree of activation of platelets. METHODS AND ANALYSIS: Our pilot prospective and descriptive study will include 50 consecutive patients hospitalized for an ischaemic stroke. We expect to identify ultrastructural characteristics that will be correlated with the degree of platelet activation to guide clinicians in decision making regarding the antiplatelet therapy strategy. ETHICS AND DISSEMINATION: The French Ethics Committee (comité de protection des personnes d'Ile-de-France VII) approved the information notice that will be given to participants and the protocol of this trial (protocol No 21-031).The results of the trial will be disseminated through scientific publications. TRIAL REGISTRATION NUMBER: NCT05004233.

The impact of advanced age on anticoagulant therapy for acute venous thromboembolism.

INTRODUCTION: Management of venous thromboembolic events (VTE) has been completely changed after the introduction of direct oral anticoagulants (DOAC). VTE is common in the geriatric population, but the management of DOACs remains complex because of the lack of specific data in this polymedicated fragile population.An exhaustive search of anticoagulants in the indication of VTE was performed on PubMed, including data from clinical trials, observational studies, real-world data, drug-drug interaction studies, as well as various guidelines from scientific societies. AREAS COVERED: The present review aims to summarize our current knowledge on the era of DOACs in the management of VTE in the elderly. This involves learning the pharmacokinetics/pharmacodynamics of drugs specific to geriatrics, the problem of drug-drug interactions, and the main randomized clinical trials validating the use of DOACs. EXPERT OPINION: DOACs have become an essential part of the management of VTE in the elderly, both for their efficacy and safety. However, we are faced with a list of unmet needs, such as the relevance of DOACs in the very elderly, cancer patients, and those with renal impairment. Clinicians and pharmacists must remain cautious about comedications, as well as about the patient's comorbidities.

Platelets as Key Factors in Inflammation: Focus on CD40L/CD40.

Platelets are anucleate cytoplasmic fragments derived from the fragmentation of medullary megakaryocytes. Activated platelets adhere to the damaged endothelium by means of glycoproteins on their surface, forming the platelet plug. Activated platelets can also secrete the contents of their granules, notably the growth factors contained in the α-granules, which are involved in platelet aggregation and maintain endothelial activation, but also contribute to vascular repair and angiogenesis. Platelets also have a major inflammatory and immune function in antibacterial defence, essentially through their Toll-like Receptors (TLRs) and Sialic acid-binding immunoglobulin-type lectin (SIGLEC). Platelet activation also contributes to the extensive release of anti- or pro-inflammatory mediators such as IL-1ß, RANTES (Regulated on Activation, Normal T Expressed and Secreted) or CD154, also known as the CD40-ligand. Platelets are involved in the direct activation of immune cells, polynuclear neutrophils (PNNs) and dendritic cells via the CD40L/CD40 complex. As a general rule, all of the studies presented in this review show that platelets are capable of covering most of the stages of inflammation, primarily through the CD40L/CD40 interaction, thus confirming their own role in this pathophysiological condition.