Observatory of Invasive Procedures and Bleeding in Patients Treated With New Oral Anticoagulants

Study Overview
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Brief Summary
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The arrival on the market of direct oral factor Xa and factor IIa inhibitors (dabigatran (Pradaxa®), rivaroxaban (Xarelto®), apixaban (Eliquis®) and others soon to come) raises novel questions among clinicians confronted with the emergency management of patients treated with these new drugs. It is likely that these new oral anticoagulants (NOACs) will eventually win a significant market share in the indications secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with nonvalvular atrial fibrillation, due to their net clinical benefit and their practicality of use compared with vitamin K antagonists (VKAs). However, despite the fact that NOACs reduce the incidence of intracranial bleeding by about half compared with VKAs, the risk remains significant; furthermore, in clinical trials, these drugs had little or no effect on reducing the incidence of major extracranial bleeding. In everyday practice, where the indication could be expanded to unselected populations and due to a potential for misuse, it is likely that the incidence of bleeding complications will be higher than that reported in clinical trials. Indeed, the numerous alerts emanating from regulatory agencies in various countries (US, Australia, etc.) bear witness to this, and should serve as a reminder that these anticoagulants have a real potential for bleeding complications and, in the absence of an antidote, there is no validated management strategy. Furthermore, as these drugs can be prescribed for months or years, patients may eventually be exposed to situations at high hemorrhagic risk, such as emergency surgery or invasive procedures, trauma, etc. Analysis of data from the trial : dabigatran versus warfarin in patients with atrial fibrillation (RE-LY) showed that during the two years of follow-up, approximately 25% of the patients underwent an invasive procedure, ranging from pacemaker insertion to major surgery. Thus, a large proportion of patients treated with NOACs are concerned by this issue. In anticipation of a gradually increasing influx of patients in a critical situation (active bleeding or need to rapidly secure hemostasis before an invasive procedure), it is urgent to define the conduct to adopt based on the experience gained from the earliest cases. This is the objective of the French-speaking GIHP-NACO observatory set up by the GIHP (French Working Group on Perioperative Hemostasis). For the moment, then, the management recommendations derive from expert opinions based on pharmacokinetic data and on the partial correction of NOAC-induced hypocoagulability by various nonspecific procoagulants (non-activated or activated prothrombin complex concentrates, recombinant factor VIIa). These procoagulants are currently used in an empirical manner to control bleeding, with as many successes as failures reported in the literature, and their benefit-risk ratio in these patients is therefore uncertain.

Detailed Description
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The management of critical situations is difficult for several reasons: First, there is significant intra- and inter-individual variability in the pharmacokinetics of NOACs, which is further heightened in the critical setting by drug interactions with other agents that interfere with P-GLYCOPROTEIN (P-GP) and cytochrome ( cytochrome P4503A4) in patients who are often elderly and multi medicated, and by rapid variations in renal function, which is essential for elimination of NOACs. Second, biological guidance is weak: there is no clearcut therapeutic range nor any validated hemostatic safety cutoff, as is the case with the International Normalized Ratio (INR) for VKAs. Conventional coagulation tests (PT/aPTT) are poorly standardized and difficult to interpret. Assays to measure the serum concentrations of these drugs are not widespread outside of a few teaching hospitals. Third, there is a lack of clinical experience. Analyses of critical situations that occurred during clinical trials were done after the fact and the data collected are heterogeneous and incomplete. Clinical cases reported in the literature are rarely well documented. The objective of the observatory is to rapidly acquire documented and thorough feedback on clinical experience with these new drugs that will be able to confer a higher level of evidence to the management recommendations for treated patients.

Official Title
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Observatory of Invasive Procedures and Bleeding in Patients Treated With New Oral Anticoagulants

Conditions
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Atrial Fibrillation, Venous Thromboembolism

Intervention / Treatment
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* Other: complications and compliance with GIHP recommendations


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Managed in view of surgery or an invasive procedure, emergency or not Managed and hospitalized for active bleeding Long-term therapy (in the indication atrial fibrillation or treatment of pulmonary embolism or deep vein thrombosis) by at least one antithrombotic agent from the following list: DABIGATRAN ETEXILATE MESYLATE or RIVAROXABAN or APIXABAN Exclusion Criteria: Pregnant women Refusal to participate in the study: listed in the non-inclusion registry Antithrombotics indicated for the prevention of venous thromboembolism

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| complications and compliance with GIHP recommendations<br>Description at 1 month post-intervention of an potential event | Other: complications and compliance with GIHP recommendations<br>* Description of complications, compliance, major bleeding events, treatments, reversal strategies.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| complications and compliance with GIHP recommendations | Association between the incidence rate at 1 month post-intervention of an event among the following complications and compliance with GIHP recommendations (appended) evaluated by a composite endpoint Major cardiovascular event ( acute coronary syndrome, cardiogenic shock, stroke or Transient Ischemic Attack (TIA), Central Nervous System (extra-CNS) thromboembolic event). Major bleeding event in the group of patients who had an emergency invasive procedure. Continued bleeding after management (treatment, reversal) in the group of patients managed for bleeding. Compliance with GIHP recommendations (appended) evaluated by a composite endpoint based on: Observance of reversal strategies Observance of the therapeutic window between the last administration and the procedure, in cases where the NOAC was stopped | At 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NOAC management | All NOAC treatments will be recorded | during the perioperative period | 
| reversal strategies description | use or not of reversal strategies will be described | during the perioperative period | 
| Coagulation test results | Coagulation test results will be recorded | during the perioperative period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haemorrhage, Oral anticoagulants, Surgery, Emergency