Clinical trial NCT02185027: Observatory of Invasive Procedures and Bleeding in Patients Treated With New Oral Anticoagulants
Official title: Observatory of Invasive Procedures and Bleeding in Patients Treated With New Oral Anticoagulants
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Venous Thromboembolism
Atrial Fibrillation
Keywords: Oral anticoagulants
Surgery
Haemorrhage
Emergency
Lead sponsor: University Hospital, Grenoble
Sponsor class: OTHER
Collaborators: name: Floralis
First posted: 2014-07-09
Enrollment: 1166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Subjects managed in view of surgery or an invasive procedure, emergency or not managed and hospitalized for active bleeding with a long-term therapy (in the indication atrial fibrillation or treatment of pulmonary embolism or deep vein thrombosis) by one antithrombotic agent (Dabigatran, Rivaroxaban, Apixaban)

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: complications and compliance with GIHP recommendations
timeFrame: At 1 month
Secondary outcomes:
measure: NOAC management
timeFrame: during the perioperative period
measure: reversal strategies description
timeFrame: during the perioperative period
measure: Coagulation test results
timeFrame: during the perioperative period
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: CHU Brugmann
city: Thonon-les-Bains
country: France
facility: Hôpitaux du Léman
state: haute-Savoie
city: Agen
country: France
facility: CH Agen
city: Amiens
country: France
facility: CHU d'Amiens
city: Annecy
country: France
facility: CHR Annecy
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Castres
country: France
facility: CH Castres
city: Chambery
country: France
facility: CH Chambéry
city: Clermont-ferrand
country: France
facility: CHU Clermont-Ferrand
city: Contamine-sur-Arve
country: France
facility: CH Alpes leman
city: Dijon
country: France
facility: CHU Dijon
city: GAP
country: France
facility: CH Gap
city: Grenoble
country: France
facility: CHU de Grenoble
city: Grenoble
country: France
facility: Groupe Hospitalier Mutualiste Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: HCL - Edouard Herriot
city: Lyon
country: France
facility: HCL - Hôpital de la Croix-Rousse
city: Lyon
country: France
facility: HCL - Lyon Sud
city: Marseille
country: France
facility: CHU Marseille
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: Centre Emile Gallé - SINCAL
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Nimes
country: France
facility: CHU Nimes
city: Niort
country: France
facility: CH de Niort
city: Paris
country: France
facility: APHP - Antoine Beclere
city: Paris
country: France
facility: APHP - Tenon
city: Paris
country: France
facility: APHP Henri Mondor
city: Paris
country: France
facility: APHP Hôpital Bichat
city: Paris
country: France
facility: APHP Hôpital Cochin
city: Paris
country: France
facility: APHP Site St Antoine
city: Paris
country: France
facility: Aphp-Hegp
city: Paris
country: France
facility: APHP-Hôpital Beaujon
city: Paris
country: France
facility: Centre Hôpital Américain
city: Paris
country: France
facility: CHU Bicêtre
city: Rennes
country: France
facility: CHU Rennes
city: Strasbourg
country: France
facility: CHRU Strasbourg - Hôpital Civil
city: Toulon
country: France
facility: Hôpital d'Instruction des Armées Sainte-Anne
city: Toulouse
country: France
facility: CHU Toulouse
city: Voiron
country: France
facility: CH Voiron
Study officials:
affiliation: University Hospital, Grenoble
name: Pierre Albaladejo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sie P; Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis. 2013 Jun-Jul;106(6-7):382-93. doi: 10.1016/j.acvd.2013.04.009. Epub 2013 Jun 25.
citation: Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012 Aug;108(2):217-24. doi: 10.1160/TH12-03-0179. Epub 2012 May 25.
citation: Sie P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV, Van der Linden P, Pernod G, Lecompte T, Gouin-Thibault I, Albaladejo P; Working Group on Perioperative Haemostasis; French Study Group on Thrombosis and Haemostasis. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis. 2011 Dec;104(12):669-76. doi: 10.1016/j.acvd.2011.09.001. Epub 2011 Oct 29.
citation: Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, Themeles E, Heidbuchel H, Avezum A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M; RE-LY Investigators. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation. 2012 Jul 17;126(3):343-8. doi: 10.1161/CIRCULATIONAHA.111.090464. Epub 2012 Jun 14.
citation: Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013 May;15(5):625-51. doi: 10.1093/europace/eut083.
citation: Godon A, Gabin M, Levy JH, Huet O, Chapalain X, David JS, Tacquard C, Sattler L, Minville V, Memier V, Blanie A, Godet T, Leone M, De Maistre E, Gruel Y, Roullet S, Vermorel C, Samama CM, Bosson JL, Albaladejo P; GIHP-NACO Study Group. Management of urgent invasive procedures in patients treated with direct oral anticoagulants: An observational registry analysis. Thromb Res. 2022 Aug;216:106-112. doi: 10.1016/j.thromres.2022.06.005. Epub 2022 Jun 22.