Major hæmorrhagePhase 3RATHERNCT02091479
Early Versus Late Resumption of Anticoagulation in Patients With Both High Thrombosis Risk and Major HEmoRrhage
A Phase 3 study testing UFH Early group and UFH Late group in people with Major hæmorrhage, run by Centre Hospitalier Universitaire de Saint Etienne at 2 sites in France.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Major hæmorrhage
- What is being tested?
- UFH Early group and UFH Late group
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 2 sitesFrance
- Study dates
- Jan 2013to Jun 2015
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
None listed.
Who cannot join
- 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
Show all 12Show fewer
- 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
Trial locations and contacts
2 sites in 1 country.
France2 sites
CHU de Saint-Etienne
Saint-Etienne, Saint-etienne, 42000
Service d'Urgences et de Réanimation Medicale, CHU de Saint-Etienne
Saint-Etienne, 42055
About this study
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.
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.
Read more
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.
Read the 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
- Major hæmorrhage
- Being tested
- UFH Early group, UFH Late group
- Keywords
- hæmorrhage, thrombosis
- Medical subject headings
- Thrombosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
UFH Early groupDrug
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).
UFH Late groupDrug
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).
| Study group | Role | What they receive |
|---|---|---|
| UFH Early group | Experimental | anticoagulant (UFH or LMWH) reintroduction at 48h to 72h after hemorrhage Receives: Drug: UFH Early group |
| UFH Late group | Active comparator | anticoagulant (UFH or LMWH) réintroduction 120h to 144h after hemorrhage Receives: Drug: UFH Late group |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: The main criterion in this study is the cumulated incidence of mortality, hæmorrhage recurrence and thromboembolic complications at 1 month
Secondary outcomes (1)
-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.
Measured: We will evaluate at 1 month and at 3 monthsthe risk/benefit balance of early versus late resumption of anticoagulant treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Mar 2014 (estimated)
- Study startJan 2013
- Primary completionJun 2015
- Study completionJun 2015
Why it stopped: inclusion rate insufficient
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major hæmorrhageStudies of the same condition, open and under way.
- More trials run by Centre Hospitalier Universitaire de Saint EtienneThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Bernard Tardy, MD phD, Principal investigator, Centre Hospitalier Universitaire de Saint Etienne
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02091479
- Sponsor's protocol ID
- 1108097
- Other IDs
- 2012-000286-21
- Acronym
- RATHER
- Status last verified
- Mar 2016
- First submitted
- 7 Mar 2014
- Last updated
- 10 Mar 2016
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 10 Mar 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT02091479
- Acronym / sponsor ID
- RATHER / 1108097
- Conditions
- Major hæmorrhage
- Keywords
- hæmorrhage, thrombosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: inclusion rate insufficient
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Centre Hospitalier Universitaire de Saint EtienneUniversity, hospital or other
- Study start
- Jan 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Jun 2015 (actual)
- First posted
- 19 Mar 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| UFH Early group | Experimental | Drug: UFH Early groupanticoagulant (UFH or LMWH) reintroduction at 48h to 72h after hemorrhage |
| UFH Late group | Active comparator | Drug: UFH Late groupanticoagulant (UFH or LMWH) réintroduction 120h to 144h after hemorrhage |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (0 listed)
Key exclusion criteria (12 listed)
- intracranial bleeding
- artificial heart valves
- bleeding with hemostatic surgical
- low and moderate thrombosis risk
- INR>1.2
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| UFH Early groupEither 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). | Drug | UFH Early group |
| UFH Late groupEither 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). | Drug | UFH Late group |
Primary outcome
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
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.
1 secondary outcome
-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
Results and safety
The study was stopped early (reason given: inclusion rate insufficient). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Mar 2016.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bernard Tardy, MD phD principal investigator
Centre Hospitalier Universitaire de Saint Etienne
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing UFH Early group and UFH Late group in people with Major hæmorrhage, run by Centre Hospitalier Universitaire de Saint Etienne at 2 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 10 Mar 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: inclusion rate insufficient). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Mar 2016.