Reversal Agent Use in Patients Treated With Direct Oral Anticoagulants or Vitamin K Antagonists (RADOA). Focus on New Antidots

Prospective, Observational, Non-interventional Open-Label, International, Multicenter Registry Regarding the Management of Severe Bleeding and/or Urgent Interventions During Treatment With Direct Oral Anticoagulants or Vitamin K Antagonists

Patients treated with Vitamin K antagonists (VKA) or direct oral anticoagulants as Rivaroxaban, Apixaban, Edoxaban or Dabigatran, who experience severe bleeding and/or need urgent interventions/operations that cannot wait are included in this registry, or during emergency operations

Study Overview

• Status: Withdrawn
• Conditions: Urgent Surgery; Severe Bleeding
• Intervention / Treatment: Procedure: Urgent surgery which can not be postponed to the next 24 hrs

Detailed Description

The Registry will offer the opportunity to evaluate the effects of reversal agents as PCC, aPCC, rVIIa, specific antidots in patients needing urgent interventions/operations or in severe bleeding patients treated with oral anticoagulants.

By collecting case reports from several university hospitals and clinics, different treatment strategies in clinical practice will be observed and evaluated, and may serve as a comprehensive information resource for the safe management with DOA, but also with the long-term anticoagulation based on coumarin derivatives in the near future.

The current objective of this registry is to:

1. Document the clinical course and outcome of various clinical bleeding events associated with DOA or VKA in patients with severe life-threatening bleeding making intervention necessary
2. Document the clinical course and outcome of urgent surgical interventions within 24 hours after admission in patients under DOA or VKA treatment.

3. Characterisation of therapeutic strategies in stopping acute life-threatening bleeding including following agents and methods:

   1. blood transfusion,
   2. platelet concentrates
   3. reversal agents [e.g. vitamin K, prothrombin complex concentrate (PCC), activated PCC (aPCC), activated factor VII (aVII), fibrinogen concentrate, fresh frozen plasma (FFP)]
   4. specific antidots, e.g. idarucizumab, Andexanet alpha
   5. haemodialysis
   6. desmopressin
   7. tranexamic acid
   8. no specific treatment in respect to the above mentioned treatments (e.g. stop of medication and waiting until anticoagulant effect of DOA is decreased).

• Study Type: Observational

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Expected number of patients estimated by study duration

N= 130 patients treated with direct oral anticoagulants (DOA) with acute bleeding N= 130 treated with vitamin K antagonists (VKA) with acute bleeding

N= 65 patients treated with direct oral anticoagulants (DOA) with urgent surgical intervention N= 65 patients treated with vitamin K antagonists (VKA) with urgent surgical intervention

Description

Inclusion Criteria:

Group a) Bleeding patients:

• Anticoagulated patients with DOA or VKA with clinically overt major bleeding according to a specified ISTH definition for non-surgical patients:
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome
• Bleeding causing a fall in hemoglobin level of 2 g L-1 (1.24 mmol L-1 ) or more leading to transfusion of two or more units of whole blood or red cells.

OR

Group b) Acute surgical need patients

• treated with DOA or VKA and who need urgent operation which cannot wait (< 24 h after last intake of drug)
• with or without reversal agent use (e.g. PCC, aPCC, rVIIa) (and/or haemodialysis for dabigatran)
• provides informed consent after the acute event

Exclusion Criteria for Group a and b:

• Conscious patient by him-/ herself or his/ her available legal representative does not agree with inclusion in the registry
• Age < 18 years
• Concomitant participation in an interventional trial

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
DOA; N= 130 patients treated with direct oral anticoagulants (DOAC) with acute bleeding N= 65 patients treated with direct oral anticoagulants (DOAC) with urgent surgical intervention	Procedure: Urgent surgery which can not be postponed to the next 24 hrs; The urgent surgical intervention is not part of the registry protocol. The intervention is the acute event that leads to enrollment in the registry. It might be e.g. the surgical treatment of a trauma, fall, acute abdomen, appendicitis or anything else.
VKA; N= 130 patients treated with vitamin K antagonists (VKA) with acute bleeding N= 65 patients treated with vitamin K antagonists (VKA) with urgent surgical intervention	Procedure: Urgent surgery which can not be postponed to the next 24 hrs; The urgent surgical intervention is not part of the registry protocol. The intervention is the acute event that leads to enrollment in the registry. It might be e.g. the surgical treatment of a trauma, fall, acute abdomen, appendicitis or anything else.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In hospital mortality up to 30 days after admission	Death rate (number of deaths)	up to 30 days after hospital admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stop of bleeding defined according to the treating physicians	Decission according to the treating physicians	up to 30 days after hospital admission
Fatality rate caused by unstoppable bleeding	Death rate (number of deaths)	up to 30 days after hospital admission
Use versus no use of reversal agents - difference in outcome?	documentation of use of reversal agents in eCRF	up to 30 days after hospital admission
Definition of supportive measures being effective in stopping bleeding	documentation of supportive measures in eCRF	up to 30 days after hospital admission
Effectiveness of dialysis vs. no dialysis in case of dabigatran accumulation associated with bleeding	time frame until stop of bleeding	up to 30 days after hospital admission
Causality assessment: Relation of SAE to anticoagulant medication	Decission according to the treating physicians	up to 30 days after hospital admission
Blood loss, number of transfusions necessary	documentation of supportive measures in eCRF	up to 30 days after hospital admission
Satisfaction of surgeon during and after surgery concerning bleeding	Decission according to the treating physicians	up to 30 days after hospital admission
Use versus no use of reversal agents - difference in blood loss and number of transfusions	documentation of supportive measures in eCRF	up to 30 days after hospital admission
Delay in performance of surgery due to anticoagulation	time Frame documented in eCRF	up to 30 days after hospital admission

Collaborators and Investigators

• Sponsor: Cardioangiologisches Centrum Bethanien
• Investigators: Principal Investigator: Edelgard Lindhoff-Last, Prof., CCB Studienzentrum GmbH

Publications and helpful links

General Publications

• Lindhoff-Last E, Herrmann E, Lindau S, Konstantinides S, Grottke O, Nowak-Goettl U, Lucks J, Zydek B, Heymann CV, Birschmann I, Sumnig A, Beyer-Westendorf J, Schellong S, Meybohm P, Greinacher A. Severe Hemorrhage Associated With Oral Anticoagulants. Dtsch Arztebl Int. 2020 May 1;117(18):312-319. doi: 10.3238/arztebl.2020.0312.

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2020
• Primary Completion (Anticipated): April 1, 2022
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 25, 2018

Study Record Updates

• Last Update Posted (Actual): July 17, 2020
• Last Update Submitted That Met QC Criteria: July 15, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: hemodialysis; rivaroxaban; apixaban; edoxaban; urgent surgery; dabigatran; PCC; severe bleeding; aPCC; rVIIa; antidots; idarucizumab; andexanet alpha
• Additional Relevant MeSH Terms: Pathologic Processes; Hemorrhage
• Other Study ID Numbers: RADOA.DOT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No