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

Atrial Fibrillation Clinical Trial

— GIHP-NACO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02185027
• Other study ID #: DCIC 13 18
• Status: Completed
• Start date: June 2013
• Est. completion date: December 2016

Study information

• Verified date: January 2018
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1166
• Est. completion date: December 2016
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Thromboembolism
• Venous Thromboembolism

Intervention

Other:
• complications and compliance with GIHP recommendations
Description of complications, compliance, major bleeding events, treatments, reversal strategies.

Locations

Country	Name	City	State
Belgium	CHU Brugmann	Brussels
France	CH Agen	Agen
France	CHU d'Amiens	Amiens
France	CHR Annecy	Annecy
France	CHU Besançon	Besançon
France	CHU Bordeaux	Bordeaux
France	CH Castres	Castres
France	CH Chambéry	Chambery
France	CHU Clermont-Ferrand	Clermont-ferrand
France	CH Alpes leman	Contamine-sur-Arve
France	CHU Dijon	Dijon
France	CH Gap	GAP
France	CHU de Grenoble	Grenoble
France	Groupe Hospitalier Mutualiste Grenoble	Grenoble
France	CHRU Lille	Lille
France	HCL - Edouard Herriot	Lyon
France	HCL - Hôpital de la Croix-Rousse	Lyon
France	HCL - Lyon Sud	Lyon
France	CHU Marseille	Marseille
France	CHU Montpellier	Montpellier
France	Centre Emile Gallé - SINCAL	Nancy
France	CHU Nancy	Nancy
France	CHU Nantes	Nantes
France	CHU Nimes	Nimes
France	CH de Niort	Niort
France	APHP - Antoine Beclere	Paris
France	APHP - Tenon	Paris
France	APHP Henri Mondor	Paris
France	APHP Hôpital Bichat	Paris
France	APHP Hôpital Cochin	Paris
France	APHP Site St Antoine	Paris
France	Aphp-Hegp	Paris
France	APHP-Hôpital Beaujon	Paris
France	Centre Hôpital Américain	Paris
France	CHU Bicêtre	Paris
France	CHU Rennes	Rennes
France	CHRU Strasbourg - Hôpital Civil	Strasbourg
France	Hôpitaux du Léman	Thonon-les-Bains	haute-Savoie
France	Hôpital d'Instruction des Armées Sainte-Anne	Toulon
France	CHU Toulouse	Toulouse
France	CH Voiron	Voiron

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Grenoble	Floralis

Countries where clinical trial is conducted

Belgium,  France, 

References & Publications (5)

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. Erratum in: Circulation. 2012 Sep 4;126(10):e160. Heidbuchle, Hein [corrected to Heidbuchel, Hein]. — View 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. — View 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. Erratum in: Thromb Haemost. 2013 Jan;109(1):169. — View 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, Sié 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. — View Citation

Sié 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	NOAC management	All NOAC treatments will be recorded	during the perioperative period
Secondary	reversal strategies description	use or not of reversal strategies will be described	during the perioperative period
Secondary	Coagulation test results	Coagulation test results will be recorded	during the perioperative period