## Protocol Section
### Identification Module
**NCT ID:** NCT02091479

**Acronym:** RATHER

**Brief Title:** Early Versus Late Resumption of Anticoagulation in Patients With Both High Thrombosis Risk and Major HEmoRrhage

**Official Title:** 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.

#### Organization Study ID Info
**ID:** 1108097
#### Organization
**Class:** OTHER
**Full Name:** Centre Hospitalier Universitaire de Saint Etienne
#### Secondary ID Infos
**ID:** 2012-000286-21
**Type:** EUDRACT_NUMBER
### Status Module
#### Completion Date
**Date:** 2015-06

**Type:** ACTUAL

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2016-03-10

**Type:** ESTIMATED

**Last Update Submit Date:** 2016-03-09

**Overall Status:** TERMINATED

#### Primary Completion Date
**Date:** 2015-06

**Type:** ACTUAL

#### Start Date
**Date:** 2013-01

**Status Verified Date:** 2016-03

#### Study First Post Date
**Date:** 2014-03-19
**Type:** ESTIMATED
**Study First Submit Date:** 2014-03-07
**Study First Submit QC Date:** 2014-03-17
**Why Stopped:** inclusion rate insufficient
### Sponsor Collaborators Module

#### Lead Sponsor

**Class:** OTHER

**Name:** Centre Hospitalier Universitaire de Saint Etienne

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Oversight Has DMC:** True

### Description Module

**Brief Summary:** 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.

**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

### Conditions Module

**Conditions:**

- Major hæmorrhage

**Keywords:**

- hæmorrhage, thrombosis

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 14

**Type:** ACTUAL

**Phases:**

- PHASE3

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** anticoagulant (UFH or LMWH) reintroduction at 48h to 72h after hemorrhage

**Intervention Names:**

- Drug: UFH Early group

**Label:** UFH Early group

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** anticoagulant (UFH or LMWH) réintroduction 120h to 144h after hemorrhage

**Intervention Names:**

- Drug: UFH Late group

**Label:** UFH Late group

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- UFH Early group

**Description:** 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).

**Name:** UFH Early group

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- UFH Late group

**Description:** 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).

**Name:** UFH Late group

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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.

**Measure:** The main criterion in this study is the cumulated incidence of mortality, hæmorrhage recurrence and thromboembolic complications at 1 month

**Time Frame:** The main criterion in this study is the cumulated incidence of mortality, hæmorrhage recurrence and thromboembolic complications at 1 month

#### Secondary Outcomes

**Description:** * 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.

**Measure:** -We will evaluate the risk/benefit balance of early versus late resumption of anticoagulant treatment,

**Time Frame:** We will evaluate at 1 month and at 3 monthsthe risk/benefit balance of early versus late resumption of anticoagulant treatment

### Eligibility Module

**Eligibility Criteria:** 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

**Maximum Age:** 90 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Locations

**Location 1:**

**City:** Saint-etienne

**Country:** France

**Facility:** CHU de Saint-Etienne

**Zip:** 42000

**Location 2:**

**City:** Saint-Etienne

**Country:** France

**Facility:** Service d'Urgences et de Réanimation Medicale, CHU de Saint-Etienne

**Zip:** 42055

#### Overall Officials

**Official 1:**

**Affiliation:** CHU SAINT ETIENNE

**Name:** Bernard Tardy, MD phD

**Role:** PRINCIPAL_INVESTIGATOR

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000010335

- Term: Pathologic Processes

- ID: D000016769

- Term: Embolism and Thrombosis

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC14

- Name: Heart and Blood Diseases

### Condition Browse Module - Browse Leaves

- ID: M9556

- Name: Hemorrhage

- Relevance: HIGH

- As Found: Hemorrhage

- ID: M16686

- Name: Thrombosis

- Relevance: HIGH

- As Found: Thrombosis

- ID: M7784

- Name: Embolism

- Relevance: LOW

- As Found: Unknown

- ID: M19128

- Name: Embolism and Thrombosis

- Relevance: LOW

- As Found: Unknown

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000013927

- Term: Thrombosis

- ID: D000006470

- Term: Hemorrhage

### Intervention Browse Module - Browse Branches

- Abbrev: FiAg

- Name: Fibrinolytic Agents

- Abbrev: AnCoag

- Name: Anticoagulants

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: Coag

- Name: Coagulants

### Intervention Browse Module - Browse Leaves

- ID: M9579

- Name: Heparin

- Relevance: LOW

- As Found: Unknown

- ID: M4244

- Name: Anticoagulants

- Relevance: LOW

- As Found: Unknown

- ID: M16676

- Name: Thrombin

- Relevance: LOW

- As Found: Unknown

- ID: M46053

- Name: Calcium heparin

- Relevance: LOW

- As Found: Unknown

- ID: M9581

- Name: Heparin, Low-Molecular-Weight

- Relevance: LOW

- As Found: Unknown

- ID: M1943

- Name: Tinzaparin

- Relevance: LOW

- As Found: Unknown

- ID: M20153

- Name: Dalteparin

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-24
