Early Versus Late Resumption of Anticoagulation in Patients With Both High Thrombosis Risk and Major HEmoRrhage (RATHER)

Randomized Assay Evaluating the Risk/Benefit of Early Versus Late Resumption of Anticoagulation in Patients With Major, Non-trauma Related Hemorrhage Occurring While on Anticoagulant Treatment for a High Risk of Thrombosis.

In patients with a high thromboembolic risk, withdrawing anticoagulant treatment is recommended in some situations, including when major hæmorrhage occurs. But withdrawing treatment can be risky. In patients on a curative dose of anticoagulant medicine, treatment withdrawal heightens the risk of thromboembolic events occurring, with potentially major consequences. For instance, mechanical valve thrombosis is fatal in 15% of patients. Resumption of anticoagulation is therefore critical in patients at high risk for thromboembolic events.

However, in these patients having presented major hæmorrhage, resumption of anticoagulation heightens the risk of hæmorrhage recurrence. This risk is even higher when the original hæmorrhage was not accessible via surgical, endoscopic or endoluminal hemostasis.

As far as investigators know, there is no data in the literature to rely on when the major hæmorrhage is not accessible via hemostatic intervention and the risk of thrombosis is high. When confronted with patients who need anticoagulation but have a high risk of hæmorrhage recurrence, the question of when treatment should be resumed has not been resolved. This is why investigators propose to conduct a randomised comparative study to evaluate two treatment strategies - early resumption (H48 to H72) versus late resumption (H120 to H144) of anticoagulation.

MAIN OBJECTIVE: The main objective of the present study is to evaluate in terms of bleeding risk, thrombosis risk and mortality at one month, the effect of early vs. late resumption of anticoagulation in patients having presented with serious hæmorrhage while on curative-dose anticoagulants and facing a high thromboembolic risk.

Study Overview

• Status: Terminated
• Conditions: Major hæmorrhage
• Intervention / Treatment: Drug: UFH Early group; Drug: UFH Late group

Detailed Description

STUDY DESIGN: This is a comparative, randomised, open study assessing after 1 month and 3 months the effect of early (H48 to 72) versus late (H120 to 144) resumption of anticoagulation in patients presenting with serious bleeding while on anticoagulants (excluding intracerebral bleeding) and with a thromboembolic risk evaluated as high (except mitral prostheses). The accumulated frequency of major hæmorrhage, thromboembolic events and deaths should be 26% in case of early resumption and 15% in case of late resumption, i.e. a relative risk reduction of 43%. Based on this hypothesis, to obtain 80% power with two-sided α being 5%, each group should include 208 patients, for a total of 416 patients.

EVALUATION CRITERIA: The main criteria in this study will be the accumulated one-month incidence of hæmorrhage recurrence, thromboembolic complications and deaths. It is a combined criterion associating:

• Fatal hæmorrhage proven by autopsy or sudden deaths in a clinical context strongly suggestive of hæmorrhage
• Fatal thromboembolic events proven by autopsy or imagery or sudden deaths in a clinical context strongly suggestive of thrombosis
• Any clinically significant hæmorrhage leading to temporary (> 24 hours) or permanent withdrawal of anticoagulant treatment
• Any symptomatic thromboembolic event in any territory, proven by imagery or surgery

These events will be validated by a committee for the validation of critical events blind to the date of anticoagulant treatment resumption. The secondary evaluation criteria will be symptomatic hæmorrhages, fatal or not, symptomatic thromboembolic incidents, fatal or not, and mortality at 1 month and 3 mont

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Saint-Etienne, France, 42055
    • Service d'Urgences et de Réanimation Medicale, CHU de Saint-Etienne
  • Saint-etienne, France, 42000
    • CHU de SAINT-ETIENNE

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:affiliated with or a beneficiary of a social security category

• age > 18 years old
• with major bleeding (ISTH) and highs thrombosis risk (ACCP 2008)
• having signed the inform consent form

Exclusion Criteria:

• intracranial bleeding
• artificial heart valves
• bleeding with hemostatic surgical
• low and moderate thrombosis risk
• INR>1.2
• hemodynamic instability contra-indication to HBPM or HNF treatment
• With previous history of HIT (heparin Inducted thrombopenia)
• patient who need antiaggregant treatment before anticoagulant treatment
• Hæmoglobin count < 8 g/dl or patients with hæmoglobin count < 10 g/dl combined with acute coronary syndrome or proven heart failure
• pregnant
• Polytraumatism
• with curatif heparin before randomisation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UFH Early group; anticoagulant (UFH or LMWH) reintroduction at 48h to 72h after hemorrhage	Drug: UFH Early group; Either curative dose, intravenous unfractionated heparin (UFH) so as to reach an anti-Xa activity between 0.3 and 0.7 IU/mL, lengthening the activated prothrombin time as determined by each centre according to the treatment area (depending on the coagulometer and reactants). Or low-molecular-weight, curative dose, subcutaneous heparin (LMWH) so as to reach an anti-Xa activity corresponding to treatment areas as determined for each type of molecule (about 0.5 to 1 anti-Xa IU for most LMWHs, administered via 2 daily injections, and about 0.5 to 1.5 anti-Xa IU for tinzaparin, 1 injection daily).
Active Comparator: UFH Late group; anticoagulant (UFH or LMWH) réintroduction 120h to 144h after hemorrhage	Drug: UFH Late group; Either curative dose, intravenous unfractionated heparin (UFH) so as to reach an anti-Xa activity between 0.3 and 0.7 IU/mL, lengthening the activated prothrombin time as determined by each centre according to the treatment area (depending on the coagulometer and reactants). Or low-molecular-weight, curative dose, subcutaneous heparin (LMWH) so as to reach an anti-Xa activity corresponding to treatment areas as determined for each type of molecule (about 0.5 to 1 anti-Xa IU for most LMWHs, administered via 2 daily injections, and about 0.5 to 1.5 anti-Xa IU for tinzaparin, 1 injection daily).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The main criterion in this study is the cumulated incidence of mortality, hæmorrhage recurrence and thromboembolic complications at 1 month	Fatal hæmorrhage proven by autopsy or sudden deaths in a clinical context strongly suggestive of hæmorrhage,; Fatal thromboembolic events proven by autopsy or imagery or sudden deaths in a clinical context strongly suggestive of thrombosis,; Any clinically significant hæmorrhage leading to temporary (> 24 hours) or permanent withdrawal of anticoagulant treatment,; Any symptomatic thromboembolic event in any territory, proven by imagery or surgery,; Any heart valve thrombosis or any intracavitary thrombus spotted by transesophageal echocardiogram performed systematically in patients with mechanical prosthesis or valvular rheumatic heart disease or AF.	The main criterion in this study is the cumulated incidence of mortality, hæmorrhage recurrence and thromboembolic complications at 1 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
-We will evaluate the risk/benefit balance of early versus late resumption of anticoagulant treatment,	Fatal hæmorrhages proven by autopsy or imagery or sudden deaths in a clinical context strongly suggestive of hæmorrhage,; Fatal thromboembolic events proven by autopsy or imagery or sudden deaths in a clinical context strongly suggestive of thrombosis,; Any clinically significant hæmorrhage leading to temporary (> 24 hours) or permanent withdrawal of anticoagulant treatment,; Any symptomatic thromboembolic event in any territory, proven by imagery or surgery,; Any heart valve thrombosis or any intracavitary thrombus spotted by transesophageal echocardiogram performed systematically in patients with mechanical prosthesis or valvular rheumatic heart disease or AF.	We will evaluate at 1 month and at 3 monthsthe risk/benefit balance of early versus late resumption of anticoagulant treatment

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Investigators: Principal Investigator: Bernard Tardy, MD phD, CHU Saint Etienne

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): June 1, 2015
• Study Completion (Actual): June 1, 2015

Study Registration Dates

• First Submitted: March 7, 2014
• First Submitted That Met QC Criteria: March 17, 2014
• First Posted (Estimate): March 19, 2014

Study Record Updates

• Last Update Posted (Estimate): March 10, 2016
• Last Update Submitted That Met QC Criteria: March 9, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: hæmorrhage, thrombosis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Hemorrhage; Thrombosis
• Other Study ID Numbers: 1108097; 2012-000286-21 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No