International Normalized Ratio (INR) Normalization in Coumadin Associated Intracerebral Haemorrhage

Study Overview
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Brief Summary
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Intracerebral haemorrhage (ICH) is the most feared complication in patients on vitamin K antagonists (VKA). VKA related ICH occurs 8-10 times more frequently and the mortality is 2 times higher than in non-anticoagulated patients. Mortality may rise up to 67%. The higher mortality rate may in part be due to the higher rate of haematoma expansion (HE) over a longer period after symptom onset. International guidelines recommend treatment of VKA-ICH with prothrombin complex (PCC) or fresh-frozen plasma (FFP) both in combination with Vitamin-K. But these recommendations are not based on randomized controlled trials. It is known that these drugs lower the INR, and thus it is assumed that normalization of coagulopathy may lead to haemostasis and reduction of HE. Safety and efficacy of these treatments have never been studied in a prospective controlled trial. The investigators' questions are: How potent are PCC and FFP in normalization of the INR? What is the safety profile of each of these drugs?

Official Title
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Multicenter, Prospective Randomized Trial on the Use of Prothrombin Complex and Fresh Frozen Plasma in Patients With Intracerebral Hemorrhage Related to Vitamin K Antagonists

Conditions
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Intracranial Hemorrhages

Intervention / Treatment
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* Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Spontaneous ICH (intraparenchymal), subdural hematoma (SDH) diagnosed by CT scanning ≤ 12 hours after onset of symptoms. In case of unknown time of symptom onset: time between last seen in healthy condition and first CCT ≤ 12 hours. Therapy receiving vitamin K antagonists (VKA) International Normalized Ratio (INR) ≥ 2 Signed informed consent form, or signed informed consent by a legal representative, judicial consent in cases where no legal representative is available in time, or consent of an independent physician familiar with the indication in cases where the first three possibilities can not be realized. Exclusion Criteria: Patients with ICH not related to vitamin-K antagonist therapy or Patients with secondary ICH related to infarction, hemophilia or other coagulopathy, tumor, hemorrhagic infarction, cerebrovenous thrombosis, aneurysm, arteriovenous malformations (AVM) or severe trauma Deep Coma (GCS ≤ 5) at the time of admission or before intubation if intubated outside the hospital Known previous disability (mRS > 2 before stroke occurred) Acute myocardial ischemia, acute septicemia, acute crush injury, any history of acute hemorrhagic disseminated intravascular coagulation, acute thrombotic stroke Known history of intermittent claudication Known recent thrombotic event < 30 days Acute or known congestive heart failure (NYHA III, IV) Pulmonary edema Known liver failure (child-pugh-score C) Known alcohol or other drug abuse Known active malignant disease Known thrombocytopenia (platelets <50,000/µL), hemorrhagic diathesis (primary defects of coagulation, fibrinolysis, platelets) History of hypersensitivity to the investigational products or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational product Known allergy to heparin or history of heparin induced thrombocytopenia. Pregnancy and lactation Concomitant use of antithrombotic (with PTT > 1.5 of normal PTT), thrombolytic treatment. Use of aspirin, clopidogrel or dipyridamole or combinations thereof (e.g. Aggrenox®) is not an exclusion criterion. These drugs should be discontinued and not restarted earlier than 24 hours after normalization of INR if indicated. Previous participation in this trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prothrombin complex concentrate (PCC)<br>intravenously, 30 IU/kg | Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP)<br>* intravenous, repeated until INR ≤ 1.2<br>|
| Experimental: Fresh frozen plasma (FFP)<br>intravenously, 20ml/kg | Drug: Prothrombin complex concentrate (PCC); fresh frozen plasma (FFP)<br>* intravenous, repeated until INR ≤ 1.2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| INR ≤ 1.2 within 3 hours after start of drug infusion |  | 3 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of thromboembolic events |  | 90 days | 
| Efficacy: Percentage of volume increase |  | 24 hours | 
| Clinical outcome |  | day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intracranial Hemorrhages, Vitamin-K antagonist, Hemostatic treatment, Prothrombin complex, Fresh frozen plasma, Intracranial Hemorrhages related to vitamin-K antagonist